Unit dose pharmaceutical of a dry powder of one or more glucocorticoid or mineralocorticoid fludrocortisone acetate and/or triamcinolone acetonide comprised in a syringe

ABSTRACT

A unit dose pharmaceutical composition comprising 2.0 to 8.0 mg of a dry powder of one or more glucocorticoid or mineralocorticoid or a therapeutically active analogue, derivative, homolog, pharmaceutically acceptable salt or conjugate thereof; wherein the composition is comprised in a syringe is disclosed. The composition may also comprise a a sterile, liquid carrier suitable for direct injection into an eye and/or 0.6 to 0.75% (w/v) of carboxy methyl cellulose (CMC); and 0.015 to 0.04 (w/v) of a surfactant. Also disclosed is a medical device comprising the unit dose pharmaceutical composition, use of the pharmaceutical composition in the treatment of an eye disease or condition or predisposition thereto and a method of treatment of an eye disease or condition or a predisposition thereto in a subject in need thereof including injecting into the eye the pharmaceutical formulation. The injection may comprise an intravitreal and/or suprachoroidal injection.

CROSS-REFERENCES TO RELATED APPLICATIONS

This application is a division of U.S. Pat. Appl. No. 16/961,617, filedJul. 10, 2020, now allowed, which is a National Stage Application under35 U.S.C. §371 of PCT/AU2019/000002, filed Jan. 9, 2019, which claimspriority to Australian Patent Appl. No. 2018900077, filed Jan. 10, 2018,the entire contents of each of these filings being incorporated byreference herein.

FIELD OF THE INVENTION

THIS INVENTION described herein relates generally to a medical device,pharmaceutical composition and method for making a pharmaceuticalcomposition for treating an eye disease or condition including adiabetic eye disease and an ocular tumour. In particular, the inventionis directed to a medical device and pharmaceutical compositioncomprising a unit dose formulation of one or more glucocorticoid ormineralocorticoid and a method of making such a pharmaceuticalcomposition.

BACKGROUND OF THE INVENTION

Triamcinolone acetonide (TA) is a synthetic corticosteroid indicated forvarious diabetic and neovascular retinal disease and inflammatoryconditions which are unresponsive to topical corticosteroids.Triamcinolone acetonide has been used as a mono-therapy and co-therapyfor various back of eye conditions and is also indicated forvisualisation during vitrectomy. Since the initial report of its use inhumans to treat exudative macular degeneration (Penfold, P.L. et al.,“Exudative macular degeneration and intra vitreal triamcinolone. A pilotstudy.” Aust. N.Z.J. Ophthalmol. 1995: 23(4):293-298), triamcinoloneacetonide is now widely used for treatment of diabetic retinopathy,uveitis and choroidal neovascularisation associated with age-relatedmacular degeneration.

Diabetic macular edema (DME) is the leading cause of visual loss indiabetic retinopathy. Intravitreal triamcinolone acetonide has been usedsuccessfully to improve visual acuity while significantly reducing DMEand also to reduce central macular thickness. Although such use isconsidered off-label in the US, many retina specialists advocate usingintravitreal triamcinolone acetonide in primary treatment of refractoryDME.

A proposed mechanism of action is that TA increases the levels oftight-junction proteins and thus diminishes vessel leakage andangiostatic actions through vascular endothelial growth factor (VEGF)inhibition. Despite having great potential, intravitreal triamcinoloneacetonide carries considerable risks including cataract formation andglaucoma.

TA is available in various different formulations. A study evaluated therate of sterile endophthalmitis (SE) following intravitreal injection ofthree different formulations of TA (Dodwell D. G. et al., Sterileendophthalmitis rates and particle size analyses of differentformulations of triamcinolone acetonide. Clin. Ophthalmol: 2015; 9:1033-1040). The three formulations evaluated were Triescence®,Kenalog®-40 and preservative-free TA. Four cases of SE were observedfollowing treatment with Triescence®. One case of SE was observedfollowing treatment with the preservative-free TA and no cases wereobserved following treatment with Kenelog®-40. Triescence has thesmallest particle size and highest particle load (number of particlesinjected).

There remains a need for alternative formulations.

SUMMARY OF THE INVENTION

The present invention has arisen after the inventors discovered animproved medical device, improved pharmaceutical composition and animproved method for making a pharmaceutical composition for thetreatment of an eye disease and/or condition or predisposition thereto.

In a broad form, the invention relates to a medical device comprising aunit dose pharmaceutical composition, a unit dose pharmaceuticalcomposition, a method for making a unit dose pharmaceutical compositionand a unit dose pharmaceutical composition for the treatment of an eyedisease or condition or predisposition thereto.

In a first aspect, the present invention is broadly directed to a unitdose pharmaceutical composition comprising: 2.0 to 8.0 mg of a drypowder of one or more glucocorticoid or mineralocorticoid or atherapeutically active analogue, derivative, homolog, pharmaceuticallyacceptable salt or conjugate thereof; wherein the unit dosepharmaceutical composition is comprised in a syringe.

In a second aspect, the present invention is broadly directed to amedical device comprising a unit dose pharmaceutical compositioncomprising: 2.0 to 8.0 mg of a dry powder of one or more glucocorticoidor mineralocorticoid or a therapeutically active analogue, derivative,homolog, pharmaceutically acceptable salt or conjugate thereof; whereinthe unit dose pharmaceutical composition is comprised in a syringe.

The composition of the first aspect or device of the second aspect mayfurther comprise a sterile, liquid carrier suitable for direct injectioninto an eye. The dry powder may be dissolved or suspended into thesterile, liquid carrier.

In a third aspect, the present invention is broadly directed to a unitdose pharmaceutical composition comprising: 2.0 to 8.0 mg of one or moreglucocorticoid or mineralocorticoid or a therapeutically activeanalogue, derivative, homolog, pharmaceutically acceptable salt orconjugate thereof; 0.6 to 0.75 % (w/v) of carboxy methyl cellulose(CMC); and 0.015 to 0.04 (w/v) of a surfactant; wherein the unit dosepharmaceutical composition is comprised in a syringe.

In a fourth aspect, the present invention is broadly directed to amedical device comprising a unit dose pharmaceutical compositioncomprising: 2.0 to 8.0 mg of one or more glucocorticoid ormineralocorticoid or a therapeutically active analogue, derivative,homolog, pharmaceutically acceptable salt or conjugate thereof; 0.6 to0.75% (w/v) of carboxy methyl cellulose (CMC); and 0.015 to 0.04 (w/v)of a surfactant; wherein the unit dose pharmaceutical composition iscomprised in a syringe.

In a fifth aspect, the present invention provides the unit dosepharmaceutical composition or the medical device of any one of thefirst, second, third or fourth aspects for use or when used in thetreatment of an eye disease or condition or predisposition thereto.

In a sixth aspect, the present invention provides a method of treatmentof an eye disease or condition or a predisposition thereto in a subjectin need thereof, the method including injecting into said eye the unitdose pharmaceutical formulation of any one of the first, second, thirdor fourth aspects. The injection may comprise intravitreal and/orsuprachoroidal injection.

According to the sixth aspect, the injection may use a double-barrelledsyringe and a first barrel and a second barrel are injectedsubstantially simultaneously.

In a seventh aspect, the present invention provides the use of the unitdose pharmaceutical composition of any one of the first to fourthaspects for the manufacture of a medicament for the therapeutic and/orprophylactic treatment of an eye disease or condition.

In an eighth aspect, the present invention provides a syringe comprisingthe unit dose pharmaceutical composition of the first or third aspects.

In one embodiment of any one of the above aspects, the syringe comprisesa 25 to 30 gauge. The gauge may comprise 25, 26, 27, 28, 29 or 30 gauge.In a particular embodiment the gauge comprises 27. The syringe maycomprise a 27 G thin wall needle.

The syringe according to any one of the above aspects may comprise avolume of 0.25 to 0.75 ml. The volume may comprise 0.25, 0.30, 0.35,0.40, 0.45, 0.50, 0.55, 0.60, 0.65, 0.70 or 0.75 ml. In a preferredembodiment volume comprises 0.50 ml.

The syringe according to any one of the above aspects may be adouble-barrelled syringe. The first barrel may comprise thepharmaceutical composition of the first or second aspect and the secondbarrel may comprise another medicament. The another medicament maycomprise an anti-VEGF (anti-Vascular Endothelial Growth Factor). Theanti-VEGF may comprise one or more of ranibizumab (brand nameLucentis®); aflibercept (brand name Eylea®); bevacizumab (brand nameAvastin®) and OPT-302.

The double-barrelled syringe according to any one of the above aspectsmay allow contents of a first barrel and a second barrel to be injectedsimultaneously or substantially simultaneously.

The volume of the pharmaceutical composition comprised in the syringeaccording to any one of the above aspects may be 0.05 to 0.15 ml. Thevolume may comprise 0.05, 0.06, 0.07, 0.08, 0.09, 0.10, 0.11, 0.12,0.13, 0.14 or 0.15 ml. In a particular embodiment, the volume comprises0.1 ml.

In another embodiment of any one of the above aspects the syringecomprises a needle comprising a length of 8 to 15 mm. The length maycomprise 8, 9, 10, 11, 12, 13, 14 or 15 mm. In a particular embodimentthe length comprises 12 mm.

In a preferred embodiment of any one of the above aspects the syringe isprefixed with a needle.

The syringe according to any one of the above aspects may comprise oneor more polymer or glass. In a particular embodiment the syringecomprises glass.

In another embodiment of any one of aspects three to eight, thepharmaceutical composition may further comprise 0.6 to 0.7 carboxymethyl cellulose (CMC). The pharmaceutical composition may comprise0.61, 0.62, 0.63, 0.64, 0.65, 0.66, 0.67, 0.68, 0.69, 0.70, 0.71, 0.72,0.73, 0.74 or 0.75% of carboxy methyl cellulose (CMC).

In still another embodiment of any one of aspects three to eight, thepharmaceutical composition may comprise 0.02 to 0.035 of a surfactant.The pharmaceutical composition may comprise 0.02, 0.021, 0.022, 0.023,0.024, 0.025, 0.026, 0.027, 0.028, 0.029, 0.030, 0.031, 0.032, 0.033,0.034, 0.35, 0.036, 0.037, 0.038, 0.039 or 0.04 of a surfactant.

The surfactant according to any one of the above aspects may comprise apolysorbate. The polysorbate may comprise one or more of polysorbate 20and polysorbate 80. In a particular embodiment the surfactant comprisespolysorbate 80.

In one embodiment of any one of the above aspects, the one or moreglucocorticoid or mineralocorticoid or a therapeutically activeanalogue, derivative, homolog, pharmaceutically acceptable salt orconjugate thereof is comprised in at least two particle sizes. The atleast two particle sizes may comprise a smaller particle size and alarger particle size. The smaller particle size may comprise less than10 µm. The larger particle size may comprise 10 to 40 µm. The largerparticle size may comprise a mean of 25 µm.

When the at least two particle sizes comprises two particle sizes, theratio may comprise 9:1; 7:1; 6:1; 5:1; 4:1; 3:1; 2:1 or 1:1.

In one embodiment of any one of the above aspects, the pharmaceuticalcomposition further comprises one or more of a pH adjustment compositionand water for injection. The pH adjustment composition may comprisehydrochloric acid and/or sodium hydroxide.

In another embodiment of any one of the above aspects the pharmaceuticalcomposition comprises a pH from 6 to 8. The pH may comprise from 6 to7.5.

In still another embodiment of any one of the above aspects thepharmaceutical composition comprises a viscosity of 2 to 15 cps. Theviscosity may comprise 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14 o5 15cps.

In yet another embodiment of any one of the above aspects thepharmaceutical composition may comprise a degree of flocculation ofabout 9.5 or greater.

In one embodiment of any one of the above aspects, the pharmaceuticalcomposition or sterile, liquid carrier suitable for direct injectioninto an eye comprises a balanced salt solution. The balanced saltsolution may comprise a saline and a buffer. The balanced salt solutionmay comprise one or more of sodium chloride; potassium chloride; calciumchloride (dehydrate); magnesium chloride (hexahydrate); sodium acetate(trihydrate); sodium citrate (dehydrate); hydrochloric acid; sodiumhydroxide and water for injection.

In another embodiment of any one of the above aspects, thepharmaceutical composition or the sterile, liquid carrier suitable fordirect injection into an eye comprises a hemp seed oil. The hemp seedoil may comprise sterile, cold pressed hemp seed oil.

In another embodiment of any one of the above aspects, the one or moreglucocorticoid or mineralocorticoid or a therapeutically activeanalogue, derivative, homolog, pharmaceutically acceptable salt orconjugate thereof comprises a mixture of one or more glucocorticoid or atherapeutically active analogue, derivative, homolog, pharmaceuticallyacceptable salt or conjugate thereof and one or more mineralocorticoidor a therapeutically active analogue, derivative, homolog,pharmaceutically acceptable salt or conjugate thereof. The mixture maycomprise: two or more glucocorticoids; one or more mineralocorticoid andone or more glucocorticoids; or two or more mineralocorticoids.

In another embodiment of any one of the above aspects, thepharmaceutical composition may comprise 2.0 to 8.0 mg of the one or moreglucocorticoid or mineralocorticoid or a therapeutically activeanalogue, derivative, homolog, pharmaceutically acceptable salt orconjugate thereof. The pharmaceutical composition may comprise 0.4; 0.5,0.6, 0.7, 0.8, 0.9, 1.0, 1.1, 1.2, 1.3, 1.4, 1.5, 1.6, 1.7, 1.8, 1.9,2.0, 2.1, 2.2, 2.3, 2.4, 2.5, 2.6, 2.7, 2.8, 2.9, 3.0, 3.1, 3.2, 3.3,3.4, 3.5, 3.6, 3.7, 3.8, 3.9, 4.0, 4.1, 4.2, 4.3, 4.4, 4.5, 4.6, 4.7,4.8, 4.9, 5.0, 5.1, 5.2, 5.3, 5.4, 5.5, 5.6, 5.7, 5.8, 5.9, 6.0, 6.1,6.2, 6.3, 6.4, 6.5, 6.6, 6.7, 6.8, 6.9, 7.0, 7.1, 7.2, 7.3, 7.4, 7.5,7.6, 7.7, 7.8, 7.9 or 8.0 mg of the one or more glucocorticoid ormineralocorticoid or a therapeutically active analogue, derivative,homolog, pharmaceutically acceptable salt or conjugate thereof. Inparticular embodiments, the pharmaceutical composition comprises 400 µg;1.0 mg; 2.0 mg; or 4.0 mg of the one or more glucocorticoid ormineralocorticoid or a therapeutically active analogue, derivative,homolog, pharmaceutically acceptable salt or conjugate thereof.

In still another particular embodiment of any one of the above aspects,the concentration of the one or more glucocorticoid or mineralocorticoidor a therapeutically active analogue, derivative, homolog,pharmaceutically acceptable salt or conjugate thereof may be 20, 21, 22,23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40,41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58,59, 60, 61, 62, 63, 64, 65, 66, 67, 68, 69, 70, 71, 72, 73, 74, 75, 76,77, 78, 79 or 80 mg/ml. In a particular embodiment, the concentrationcomprises 40 mg/ml.

In a particular embodiment of any one of the above aspects, the one ormore glucocorticoid or mineralocorticoid or a therapeutically activeanalogue, derivative, homolog, pharmaceutically acceptable salt orconjugate thereof may comprise 0.1 ml of a 40 mg/ml solution.

In other particular embodiments of any one of the above aspects, theconcentration of the one or more glucocorticoid or mineralocorticoid ora therapeutically active analogue, derivative, homolog, pharmaceuticallyacceptable salt or conjugate thereof may be 400 µg/0.1 mL; 1 mg/0.1 mL;or 2 mg/0.1 mL.

In another particular embodiment of any one of the above aspects, thepharmaceutical composition is preservative free.

According to any one of the above aspects, the glucocorticoid maycomprise one or more of: cortisol, cortisone, prednisone, prednisolone,methylprednisolone, dexamethasone, betamethasone, triamcinolone,triamcinolone acetonide, beclometasone or a therapeutically activeanalogue, derivative, homolog, pharmaceutically acceptable salt orconjugate thereof.

The mineralocorticoid according to any one of the above aspects, theglucocorticoid or mineralocorticoid or a therapeutically activeanalogue, derivative, homolog, pharmaceutically acceptable salt orconjugate thereof may comprise one or more of: 11-desoxycortisone(11-DC); fludrocortisone; fludrocortisone acetate (FA);Deoxycorticosterone acetate (DA); Deoxycorticosterone (DS); orAldosterone; or a therapeutically active analogue, derivative, homolog,pharmaceutically acceptable salt or conjugate thereof.

The one or more glucocorticoid or mineralocorticoid or a therapeuticallyactive analogue, derivative, homolog, pharmaceutically acceptable saltor conjugate thereof according to any one of the above aspects maycomprise one or more dual action compounds, wherein each dual actioncompound is capable of modulating the activity of both amineralocorticoid receptor and a glucocorticoid receptor.

According to any of the above aspects, the dual action compound maycomprise one or more of triamcinolone acetonide; cortisol; cortisone;prednisone; prednisolone; methylprednisolone; fludrocortisone;fludrocortisone acetate or a therapeutically active analogue,derivative, homolog, pharmaceutically acceptable salt or conjugatethereof.

In one particular embodiment of any one of the above aspects, the one ormore glucocorticoid or mineralocorticoid or a therapeutically activeanalogue, derivative, homolog, pharmaceutically acceptable salt orconjugate thereof comprises triamcinolone acetonide or a therapeuticallyactive analogue, derivative, homolog, pharmaceutically acceptable saltor conjugate thereof. When the one or more glucocorticoid ormineralocorticoid or a therapeutically active analogue, derivative,homolog, pharmaceutically acceptable salt or conjugate thereof comprisestriamcinolone acetonide the concentration may comprise 3.0 to 5.0 mg/ml.In one particular embodiment the concentration may comprise 4.0 mg/ml.

In another particular embodiment of any one of the above aspects, theone or more glucocorticoid or mineralocorticoid or a therapeuticallyactive analogue, derivative, homolog, pharmaceutically acceptable saltor conjugate thereof comprises fludrocortisone acetate or atherapeutically active analogue, derivative, homolog, pharmaceuticallyacceptable salt or conjugate thereof.

In another particular embodiment of any one of the above aspects, theone or more glucocorticoid or mineralocorticoid or a therapeuticallyactive analogue, derivative, homolog, pharmaceutically acceptable saltor conjugate thereof comprises triamcinolone acetonide andfludrocortisone acetate or a therapeutically active analogue,derivative, homolog, pharmaceutically acceptable salt or conjugate ofeither or both.

In another particular embodiment of any one of the above aspects, theone or more glucocorticoid or mineralocorticoid or a therapeuticallyactive analogue, derivative, homolog, pharmaceutically acceptable saltor conjugate thereof comprises triamcinolone acetonide andfludrocortisone acetate or a therapeutically active analogue,derivative, homolog, pharmaceutically acceptable salt or conjugate ofeither or both.

In yet another particular embodiment of any one of the above aspects,the pharmaceutical composition may comprise a powder. The powder maycomprise a dry powder and/or may lack any delivery vehicle.

According to any one of the above aspects, said eye disease and/orcondition or predisposition thereto may be an exudative eye diseaseand/or condition.

According to any one of the above aspects, said eye disease and/orcondition or predisposition thereto may be a back of the eye exudativeeye disease and/or condition.

According to any one of the above aspects, said eye disease and/orcondition or predisposition thereto may be a front of the eye exudativeeye disease and/or condition.

According to any one of the above aspects, said eye disease and/orcondition or predisposition thereto may be macular degenerationincluding age-related macular degeneration and wet age related maculardegeneration.

According to any one of the above aspects, said eye disease and/orcondition or predisposition thereto may be a diabetic macular edema(DME), cystoid macular edema (CMO); maculopathy; and/or an oculartumour.

The ocular tumour may comprise a retinoblastoma and/or a melanoma.

According to any one of the above aspects, said eye disease and/orcondition or predisposition thereto may be a diabetic eye disease and/orcondition.

Other eye disease and/conditions include (non-infectious)conjunctivitis, anterior uveitis and an ocular allergy.

According to any of the above aspects, the eye disease and/or conditionor predisposition thereto may comprise one or more of maculardegeneration, maculopathy including an age related maculopathy (ARM),age related macular degeneration (AMD) including both the dry(geographic atrophy) and wet (choroidal neovascularisation (CNV)), anexudative eye disease or condition, retinal pigment epitheliumdetachments (PED), forms of age related macular degeneration, a diabeticeye disease or condition including a diabetic retinopathy and diabeticmacular edema (DME), corneal neovascularisation, cyclitis, Hippel-Lindeldisease, retinopathy of prematurity (also known as retrolentalfibroplasia), pterygium, histoplasmosis, iris neovascularisation,glaucoma, glaucoma-associated neovascularisation, Purtcher’sretinopathy, ocular hypertension, macular edema, Coats’ disease, uveitisincluding anterior uveitis, Sicca syndrome, hereditary diseasesassociated with increased extra-intracellular lipidstorage/accumulation, juvenile macular degeneration, an ocular allergy,oedema secondary to vein occlusion and an ocular tumour.

According to any one of the above aspects, the eye disease and/orcondition or predisposition thereto may comprise a back of eye diseaseor conditions including an exudative back of eye exudative disease orcondition. The back of eye disease or condition may comprise an eyedisease or condition involving the retina, macular and/or fovea in theposterior region of the eye. Examples of back of eye disease includemacular oedema, such as clinical macular oedema or angiographic cystoidmacular oedema arising from various aetiologies, such as diabetes,exudative macular degeneration and macula oedema arising from lasertreatment of the retina, retinal ischemia and choroidalneovascularisation, a retinal disease, an inflammatory disease, uveitisassociated with neoplasms, such as retinoblastoma or psuedoglioma,neovascularisation following vitrectomy, a vascular disease andneovascularisation of the optic nerve.

The retinal disease may be one or more of diabetic retinopathy, diabeticretinal oedema, retinal detachment, senile macular degeneration due tosub-retinal neovascularisation and myopic retinopathy.

The vascular disease may be one or more of retinal ischemia, choroidalvascular insufficiency, choroidal thrombosis and neovascularretinopathies resulting from carotoid artery ischemia.

According to any one of the above aspects, the eye disease and/orcondition or predisposition thereto may also comprise a front of eyedisease or condition which predominantly involves the tissue at thefront of the eye, such as the cornea, iris, ciliary body and conjunctivaincluding an exudative front of eye disease or condition. The front ofeye disease may be one or more of corneal neovascularisation, a cornealdisease or opacification with an exudative or inflammatory component,diffuse lamellar keratitis, neovascularisation due to penetration of theeye or contusive ocular injury, rubosis iritis, Fuchs’ heterochromiciridocyclitis, chronic uveitis, anterior uveitis, inflammatoryconditions resulting from surgeries such as LASIK, LASEK, refractivesurgery, IOL implantation; irreversible corneal oedema as a complicationof cataract surgery, oedema as a result of insult or trauma,inflammation, infectious and non-infectious conjunctivitis,keratoconjunctivitis, iridocyclitis, iritis, scleritis, episcleritis,infectious keratitis, superficial punctuate keratitis, keratoconus,posterior polymorphous dystrophy, Fuch’s dystrophies, aphakic andpseudophakic bullous keratopathy, corneal oedema, scleral disease,ocular cicatrcial pemphigoid, pars planitis, Posner Schlossman syndrome,Behcet’s disease, Vogt-Koyanagi-Harada syndrome, hypersensitivityreactions, ocular surface disorders, conjunctival oedema, Toxoplasmosischorioretinitis, inflammatory pseudotumor of the orbit, chemosis,conjunctival venous congestion, periorbiatal cellulits, acutedacroycystitis, non-specific vasculitis, sarcoidosis and cytomegalovirusinfection.

The invention according to any above aspect may further comprise one ormore pharmaceutically acceptable carriers, diluents or excipients.

The one or more pharmaceutically acceptable carriers, diluents orexcipients may comprise one or more surfactants or wetting agent.

According to any one of the above aspects, the compositions of theinvention may comprise a sustained release composition.

In a particular embodiment of any one of the above aspects, thepharmaceutical compositions may be sterilized.

In another particular embodiment of any one of the above aspects, a unitdose comprises the pharmaceutical composition in the form in which it isto be used. The unit dose may comprise the pharmaceutical composition ina particular dose; volume; particle size; pH; viscosity; and/or degreeof flocculation. The unit dose may comprise non-reusable packaging. Thenon-reusable packaging may comprise the syringe or double-barrelledsyringe. The provision of a unit dose may decrease error and/or increaseease of use.

According to any one of the above aspects, the composition may comprisea sufficient injectability to be injected into an eye.

As used herein, except where the context requires otherwise, the term“comprise” and variations of the term, such as “comprising”, “comprises”and “comprised”, are not intended to exclude further additives,components, integers or steps.

BRIEF DESCRIPTION OF THE FIGURES

In order that the present invention may be readily understood and putinto practical effect, reference will now be made to the accompanyingillustrations, wherein like reference numerals refer to like featuresand wherein:

FIG. 1 : Solubility enhancement for MR compounds and TA in saline withaddition of hydroxy propyl β-cyclodextrin (data are mean ± sd, n=3).Top: FLU and TA; Bottom: 11-DC; DCS and DCSA.

FIG. 2 : Drug solubility in aqueous solution of Tween 80 over time whenstored at 37° C. for 72 hr (data are mean ± sd n=3 at each time point).

FIG. 3 : The effect of autoclave and gamma irradiation sterilizationprocesses on drug stability in aqueous solutions (data are mean ± sd,n=3).

FIG. 4 : Contour plots for HPLC with absorption wavelength on the y axisand retention time on the X-axis, the intensity of colour indicatesdegree of absorbance at that wavelength and retention time (λmax = 240for all compounds in this study).

FIG. 5 : Stability of MR compounds and TA in dry powder form on exposureto 25 kGy gamma irradiation.

FIG. 6 : SEM images of MR powders as received. All images are on similarscales, highlighting the gross differences between them.

FIG. 7 : Reduction in Particle Size (distribution indicated by D(v,0.5)and D(v,0.9)) for 11-DC, DCS and DCSA with homogenisation time.

DETAILED DESCRIPTION OF THE INVENTION

The invention relates to a medical device, pharmaceutical compositionand method for making a pharmaceutical composition for treating an eyedisease or condition including a diabetic eye disease and an oculartumour.

The invention is at least partly predicated on the unexpected discoverythat a prefilled syringe comprising a unit dose pharmaceuticalcomposition has significant advantages. These advantages includeimproved ease of use for the health care professional administering theinjection and greater cost-effectiveness compared to multi-dose vials.Multi-dose vials can result in a large amount of waste when regulatoryregimes only permit one use of a vial. Additionally, the tailored,single unit dose provided by the present invention is safer, more costeffective and more accurate than the multi-dose formulations.

As used herein, the term “unit dose” is used to refer to apharmaceutical composition in the form in which it is to be used. Theunit dose may comprise the pharmaceutical composition of the inventionin a particular dose; volume; particle size; pH; viscosity; and/ordegree of flocculation. The unit dose may comprise the non-reusablepackaging such as, the syringe or double-barrelled syringe.

The present invention facilitates adjunct usage of steroids with otherocular therapies. Advantageously, this minimises the number ofinjections requires by increasing the efficacy and safety of theprocedure. In some embodiments, the present invention provides asteroidal medicament in combination with one or more other oculartherapeutic, which advantageously exposes the target tissue to bothdrugs accurately and simultaneously.

In one embodiment, the unit dose formulation provided by the presentinventors, is furnished in a 27 gauge needle that has a thinner body forgood grip. The improved grip provided by the present claimed inventionmakes injection easier and reduces any risk of injection error. The 27gauge needle may comprise a 27 G thin wall needle.

In one form the invention relates to a unit dose pharmaceuticalcomposition comprising 2.0 to 8.0 mg of one or more glucocorticoid ormineralocorticoid or a therapeutically active analogue, derivative,homolog, pharmaceutically acceptable salt or conjugate thereof.

The unit dose pharmaceutical formulation may comprise 2.0 to 8.0 mg ofone or more glucocorticoid or mineralocorticoid or a therapeuticallyactive analogue, derivative, homolog, pharmaceutically acceptable saltor conjugate thereof in a dry powder form wherein the unit dosepharmaceutical composition is comprised in a syringe.

In another form the invention relates to a medical device comprising theunit dose pharmaceutical composition, the composition comprising 2.0 to8.0 mg of a dry powder of one or more glucocorticoid ormineralocorticoid or a therapeutically active analogue, derivative,homolog, pharmaceutically acceptable salt or conjugate thereof; whereinthe unit dose pharmaceutical composition is comprised in a syringe. Withthe composition comprised in a syringe, the medical device may becomprised of a syringe.

The provision of the composition or medicament as a dry powder gives theclinician of choice of vehicle. The dry powder format is of greatadvantage, because this dry powder presentation allows long term storageand stability. Once put with its vehicle, the one or more glucocorticoidor mineralocorticoid or a therapeutically active analogue, derivative,homolog, pharmaceutically acceptable salt or conjugate thereof starts todegrade. The dry powder format preserves potency and allows long termstorage so that the same potency is available at the beginning and endof a year study. This also has an advantage in terms of ease ofsterilisation and in terms of shipping, shelf life and longevity.

In some embodiments, the dry powder may be suspended in a vehicle ofchoice such as, a sterile, liquid carrier suitable for direct injectioninto an eye.

In one embodiment, the unit dose pharmaceutical composition and medicaldevice may also comprise 0.6 to 0.75% (w/v) of CMC. In anotherembodiment, the unit dose pharmaceutical composition comprises 0.6 to0.7 (w/v) CMC. The pharmaceutical composition may comprise 0.61, 0.62,0.63, 0.64, 0.65, 0.66, 0.67, 0.68, 0.69, 0.70, 0.71, 0.72, 0.73, 0.74or 0.75% (w/v) of CMC.

In one embodiment, the unit dose pharmaceutical composition and medicaldevice may comprise 0.015 to 0.04% (w/v) of a surfactant. In anotherembodiment, the surfactant is comprises at 0.02 to 0.035% (w/v). Thepharmaceutical composition may comprise 0.02, 0.021, 0.022, 0.023,0.024, 0.025, 0.026, 0.027, 0.028, 0.029, 0.030, 0.031, 0.032, 0.033,0.034, 0.35, 0.036, 0.037, 0.038, 0.039 or 0.04 (w/v) of the surfactant.

As used herein, the term “surfactant” refers to any agent, whichpreferentially absorbs to an interface between two immiscible phases,such as the interface between water and an organic polymer solution, awater/air interface or organic solvent/air interface. Surfactantsgenerally possess a hydrophilic moiety and a lipophilic moiety; suchthat, upon absorbing to microparticles, they tend to present moieties tothe external environment that do not attract similarly coated particles,thus reducing particle agglomeration. Surfactants may also promoteabsorption of a therapeutic or diagnostic agent and increasebioavailability of the agent.

The surfactant may comprise a polysorbate, such as one or more ofpolysorbate 20 and polysorbate 80. In a preferred embodiment, thesurfactant comprises polysorbate 80.

One of the particular advantages of the present invention is that theunit dose pharmaceutical composition may be comprised in a syringe.

According to the present invention the unit dose pharmaceuticalcomposition may be used in the treatment of an eye disease or conditionor predisposition thereto.

Also provided is a method of treatment of an eye disease or condition ora predisposition thereto in a subject in need thereof, the methodincluding injecting into the eye the unit dose pharmaceuticalformulation. The injection may comprise intravitreal and/orsuprachoroidal injection.

The unit dose pharmaceutical composition of the invention may also finduse in the manufacture of a medicament for the therapeutic and/orprophylactic treatment of an eye disease or condition.

The invention also provides a syringe comprising the unit dosepharmaceutical composition.

The syringe may comprise a 25 to 30 gauge. The gauge may comprise 25,26, 27, 28, 29 or 30 gauge. In a particular embodiment the gaugecomprises 27.

The syringe may comprise a volume of 0.25 to 0.75 ml. The volume maycomprise 0.25, 0.30, 0.35, 0.40, 0.45, 0.50, 0.55, 0.60, 0.65, 0.70 or0.75 ml. In a preferred embodiment volume comprises 0.50 ml.

The volume of the pharmaceutical composition comprised in the syringemay be 0.05 to 0.15 ml. The volume may comprise 0.05, 0.06, 0.07, 0.08,0.09, 0.10, 0.11, 0.12, 0.13, 0.14 or 0.15 ml. In a particularembodiment, the volume comprises 0.1 ml.

The syringe may be a double-barrelled syringe. Each barrel may have thedimensions listed above. The first barrel may comprise a pharmaceuticalcomposition of the invention and the second barrel may comprise anothermedicament. The another medicament may comprise an anti-VEGF. Theanti-VEGF may comprise one or more of ranibizumab (brand nameLucentis®); aflibercept (brand name Eylea®); bevacizumab (brand nameAvastin®) and OPT-302 available from Opthea (www.opthea.com).

The needle comprised on the syringe may comprise a length of 8 to 15 mm.The length may comprise 8, 9, 10, 11, 12, 13, 14 or 15 mm. In aparticular embodiment the length comprises 12 mm.

The syringe may be prefixed with the needle. The needle may be removableor permanently attached. In a particular embodiment, the needle ispermanently attached and the syringe is disposable.

The syringe may comprise one or more polymer or glass. In a particularembodiment the syringe comprises glass.

The one or more glucocorticoid or mineralocorticoid or a therapeuticallyactive analogue, derivative, homolog, pharmaceutically acceptable saltor conjugate thereof may be comprised in at least two particle sizes.The at least two particle sizes may comprise a smaller particle size anda larger particle size. The smaller particle size may comprise less than10 µm. The larger particle size may comprise 10 to 40 µm. The largerparticle size may comprise a mean of 25 µm.

When the at least two particle sizes comprises two particle sizes, theratio may comprise 9:1; 7:1; 6:1; 5:1; 4:1; 3:1; 2:1 or 1:1.

The pharmaceutical composition may further comprise one or more of a pHadjustment composition and water for injection. The pH adjustmentcomposition may comprise hydrochloric acid and/or sodium hydroxide.

The pharmaceutical composition may comprise a pH from 6 to 8. The pH maycomprise from 6 to 7.5.

The pharmaceutical composition may comprise a viscosity of 2 to 15 cps.The viscosity may comprise 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14 or15 cps.

The pharmaceutical composition may comprise a degree of flocculation ofabout 9.5 or greater.

The pharmaceutical composition may comprise a balanced salt solution.The balanced salt solution may comprise a saline and a buffer. Thebalanced salt solution may comprise may comprise one or more of sodiumchloride; potassium chloride; calcium chloride (dehydrate); magnesiumchloride (hexahydrate); sodium acetate (trihydrate); sodium citrate(dehydrate); hydrochloric acid; sodium hydroxide and water forinjection.

The pharmaceutical composition or the sterile, liquid carrier suitablefor direct injection into an eye may comprise a hemp seed oil such as,sterile, cold pressed hemp seed oil.

The one or more glucocorticoid or mineralocorticoid or a therapeuticallyactive analogue, derivative, homolog, pharmaceutically acceptable saltor conjugate thereof comprises a mixture of one or more glucocorticoidand one or more mineralocorticoid a therapeutically active analogue,derivative, homolog, pharmaceutically acceptable salt or conjugatethereof. The mixture may comprise: two or more glucocorticoids; one ormore mineralocorticoid and one or more glucocorticoids; or two or moremineralocorticoids.

In a particular embodiment, the one or more glucocorticoid ormineralocorticoid or a therapeutically active analogue, derivative,homolog, pharmaceutically acceptable salt or conjugate thereof comprisestriamcinolone acetonide or a therapeutically active analogue,derivative, homolog, pharmaceutically acceptable salt or conjugatethereof. When the one or more glucocorticoid or mineralocorticoid or atherapeutically active analogue, derivative, homolog, pharmaceuticallyacceptable salt or conjugate thereof comprises triamcinolone acetonidethe concentration may comprise 3.0 to 5.0 mg/ml. In one particularembodiment the concentration may comprise 4.0 mg/ml.

The pharmaceutical composition may comprise 0.2, 0.3, 0.4, 0.5, 0.6,0.7, 0.8, 0.9, 1.0, 1.1, 1.2, 1.3, 1.4, 1.5, 1.6, 1.7, 1.8, 1.9, 2.0,2.1, 2.2, 2.3, 2.4, 2.5, 2.6, 2.7, 2.8, 2.9, 3.0, 3.1, 3.2, 3.3, 3.4,3.5, 3.6, 3.7, 3.8, 3.9, 4.0, 4.1, 4.2, 4.3, 4.4, 4.5, 4.6, 4.7, 4.8,4.9, 5.0, 5.1, 5.2, 5.3, 5.4, 5.5, 5.6, 5.7, 5.8, 5.9, 6.0, 6.1, 6.2,6.3, 6.4, 6.5, 6.6, 6.7, 6.8, 6.9, 7.0, 7.1, 7.2, 7.3, 7.4, 7.5, 7.6,7.7, 7.8, 7.9 or 8.0 mg of the one or more glucocorticoid ormineralocorticoid or a therapeutically active analogue, derivative,homolog, pharmaceutically acceptable salt or conjugate thereof. In aparticular embodiment, the pharmaceutical composition comprises 400 µg;1.0 mg ; 2.0 mg or 4.0 mg of the one or more glucocorticoid ormineralocorticoid a therapeutically active analogue, derivative,homolog, pharmaceutically acceptable salt or conjugate thereof.

The concentration of the one or more glucocorticoid or mineralocorticoidor a therapeutically active analogue, derivative, homolog,pharmaceutically acceptable salt or conjugate thereof may be may be 20,21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38,39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56,57, 58, 59, 60, 61, 62, 63, 64, 65, 66, 67, 68, 69, 70, 71, 72, 73, 74,75, 76, 77, 78, 79 or 80 mg/ml. In a particular embodiment, theconcentration comprises 40 mg/ml.

The one or more glucocorticoid or mineralocorticoid or a therapeuticallyactive analogue, derivative, homolog, pharmaceutically acceptable saltor conjugate thereof may comprise 0.1 ml of a 40 mg/ml solution.

The unit dose formulation may comprise 4.0 mg of triamcinoloneacetonide.

In a particular embodiment of any above aspect, the pharmaceuticalcomposition is preservative free.

The one or more glucocorticoid or a therapeutically active analogue,derivative, homolog, pharmaceutically acceptable salt or conjugatethereof may comprise one or more of: cortisol, cortisone, prednisone,prednisolone, methylprednisolone, dexamethasone, betamethasone,triamcinolone, triamcinolone acetonide, beclometasone or atherapeutically active analogue, derivative, homolog, pharmaceuticallyacceptable salt or conjugate thereof.

The one or more mineralocorticoid may comprise one or more of:11-desoxycortisone (11-DC); fludrocortisone; fludrocortisone acetate(FA); Deoxycorticosterone acetate (DA); Deoxycorticosterone (DS); orAldosterone; or a therapeutically active analogue, derivative, homolog,pharmaceutically acceptable salt or conjugate thereof.

The one or more glucocorticoid or mineralocorticoid or a therapeuticallyactive analogue, derivative, homolog, pharmaceutically acceptable saltor conjugate thereof may comprise one or more dual action compounds,wherein each dual action compound is capable of modulating the activityof both a mineralocorticoid receptor and a glucocorticoid receptor.

The dual action compound may comprise one or more of triamcinoloneacetonide (TA); cortisol; cortisone; prednisone; prednisolone;methylprednisolone; fludrocortisone acetate or a therapeutically activeanalogue, derivative, homolog, pharmaceutically acceptable salt orconjugate thereof.

In another particular embodiment of any of the above aspects, the one ormore glucocorticoid or mineralocorticoid or a therapeutically activeanalogue, derivative, homolog, pharmaceutically acceptable salt orconjugate thereof comprises fludrocortisone acetate or a therapeuticallyactive analogue, derivative, homolog, pharmaceutically acceptable saltor conjugate thereof.

Fludrocortisone acetate (9-α-Fiuoro-11β. 17α,21-trihydroxy-4-pregnene-3, 20 dione acetate) (FCA) is a syntheticsteroid possessing a potent mineralocorticoid effect and a highglucocorticoid activity. FCA is a synthetic corticosteroid withanti-inflammatory and anti-allergic properties. FCA is amineralocorticoid receptor and glucocorticoid receptor agonist thatbinds to cytoplasmic receptors, translocates to the nucleus andsubsequently initiates the transcription of glucocorticoid-responsivegenes such as lipocortins to inhibit phospholipase A2. This prevents therelease of arachidonic acid, a precursor to prostaglandins andleukotrienes, both important mediators in the pro-inflammatory responsemechanism. In addition, this agent exerts its mineralocorticoid effecton the distal tubules and collecting ducts of the kidney by inducingpermease, an enzyme that regulates Na+ permeability in cells, therebyenhancing Na⁺ reabsorption and water retention as well as increasing K⁺,H⁺ excretion

In another particular embodiment of any of the above aspects, the one ormore glucocorticoid or mineralocorticoid or a therapeutically activeanalogue, derivative, homolog, pharmaceutically acceptable salt orconjugate thereof comprises triamcinolone acetonide and fludrocortisoneacetate or a therapeutically active analogue, derivative, homolog,pharmaceutically acceptable salt or conjugate of either.

The pharmaceutical composition may comprise a powder. The powdered formof the pharmaceutical composition lacks any delivery vehicle, i.e. noliquid is provided with the powdered form. The powdered form may beinjected as is done with the pharmaceutical composition provided with aliquid delivery vehicle. Alternatively, a liquid delivery vehicle may beadded prior to injection. The powdered form may advantageously have anextended shelf life.

As used herein, the term “eye condition” includes any eye condition suchas, early or sub-clinical stages of an eye disease.

As used herein, the term “eye disease” includes any eye disease such as,macular degeneration, maculopathy including an age related maculopathy(ARM), age related macular degeneration (AMD) including both the dry(geographic atrophy) and wet (choroidal neovascularisation (CNV)), anexudative eye disease or condition, retinal pigment epitheliumdetachments (PED), forms of age related macular degeneration, a diabeticeye disease or condition including a diabetic retinopathy and diabeticmacular edema (DME), corneal neovascularisation, cyclitis, Hippel-Lindeldisease, retinopathy of prematurity (also known as retrolentalfibroplasia), pterygium, histoplasmosis, iris neovascularisation,glaucoma, glaucoma-associated neovascularisation, Purtcher’sretinopathy, ocular hypertension, macular edema, Coats’ disease, uveitisincluding anterior uveitis, Sicca syndrome, hereditary diseasesassociated with increased extra-intracellular lipidstorage/accumulation, juvenile macular degeneration, an ocular allergy,oedema secondary to vein occlusion and an ocular tumour. The oculartumour may comprise a retinoblastoma and/or a melanoma.

The eye disease or condition may comprise a back of eye disease orconditions including an exudative back of eye exudative disease orcondition. The back of eye disease or condition may comprise an eyedisease or condition involving the retina, macular and/or fovea in theposterior region of the eye. Examples of back of eye disease includemacular oedema, such as clinical macular oedema or angiographic cystoidmacular oedema arising from various aetiologies, such as diabetes,exudative macular degeneration and macula oedema arising from lasertreatment of the retina, retinal ischemia and choroidalneovascularisation, a retinal disease, an inflammatory disease, uveitisassociated with neoplasms, such as retinoblastoma or psuedoglioma,neovascularisation following vitrectomy, a vascular disease andneovascularisation of the optic nerve. The retinal disease may be one ormore of diabetic retinopathy, diabetic retinal oedema, retinaldetachment, senile macular degeneration due to sub-retinalneovascularisation and myopic retinopathy. The vascular disease may beone or more of retinal ischemia, choroidal vascular insufficiency,choroidal thrombosis and neovascular retinopathies resulting fromcarotoid artery ischemia.

The eye disease or condition may also comprise a front of eye disease orcondition which predominantly involves the tissue at the front of theeye, such as the cornea, iris, ciliary body and conjunctiva including anexudative front of eye disease or condition. The front of eye diseasemay be one or more of corneal neovascularisation, a corneal disease oropacification with an exudative or inflammatory component, diffuselamellar keratitis, neovascularisation due to penetration of the eye orcontusive ocular injury, rubosis iritis, Fuchs’ heterochromiciridocyclitis, chronic uveitis, anterior uveitis, inflammatoryconditions resulting from surgeries such as LASIK, LASEK, refractivesurgery, IOL implantation; irreversible corneal oedema as a complicationof cataract surgery, oedema as a result of insult or trauma,inflammation, infectious and non-infectious conjunctivitis,keratoconjunctivitis, iridocyclitis, iritis, scleritis, episcleritis,infectious keratitis, superficial punctuate keratitis, keratoconus,posterior polymorphous dystrophy, Fuch’s dystrophies, aphakic andpseudophakic bullous keratopathy, corneal oedema, scleral disease,ocular cicatrcial pemphigoid, pars planitis, Posner Schlossman syndrome,Behcet’s disease, Vogt-Koyanagi-Harada syndrome, hypersensitivityreactions, ocular surface disorders, conjunctival oedema, Toxoplasmosischorioretinitis, inflammatory pseudotumor of the orbit, chemosis,conjunctival venous congestion, periorbiatal cellulits, acutedacroycystitis, non-specific vasculitis, sarcoidosis and cytomegalovirusinfection.

The pharmaceutical compositions of the invention may have a therapeuticeffect with regards to oedema, swelling and/or neovascularisation in thetumor. Glucocorticoids and mineralocorticoids are also known to reduceinflammation and to help relieve nausea when having chemotherapy.

The invention may find application to an exudative eye disease and/orcondition, a back of the eye exudative eye disease and/or condition, afront of the eye exudative eye disease and/or condition, age-relatedmacular degeneration, wet age related macular degeneration, a diabeticmacular edema (DME), cystoid macular edema (CMO); maculopathy; and/or anocular tumour. The ocular tumour may comprise a retinoblastoma and/or amelanoma. The eye disease and/or condition may be a diabetic eye diseaseand/or condition. Other eye disease and/conditions include(non-infectious) conjunctivitis, anterior uveitis and an ocular allergy.

“Prevention” or “prophylaxis,” as used herein, refers to prophylactic orpreventative measures. Those in need of prevention or prophylaxisinclude those in whom the eye disease or condition is to be prevented,and in some embodiments, may be predisposed or susceptible to the eyedisease or condition e.g. individuals with a family history of an eyedisease or condition.

Prevention or prophylaxis is successful herein if the development of aneye disease or condition is completely or partially prevented or sloweddown.

“Treatment” of a subject herein refers to therapeutic treatment. Thosein need of treatment include those already with an eye disease orcondition, as well as those in whom the progress of an eye disease orcondition is to be prevented. Hence, the subject may have been diagnosedas having the eye disease or condition or may have an eye disease orcondition or damage that is likely to progress in the absence oftreatment. Alternatively, the subject may be symptom-free, but has riskfactors for development of an eye disease or condition e.g., positivefamily history. Treatment is successful herein if the eye disease orcondition is alleviated or healed, or progression of the eye disease orcondition, including its signs and symptoms and/or structural damage, ishalted or slowed down as compared to the condition of the subject priorto administration. Successful treatment further includes complete orpartial prevention of the development of the eye disease or condition.For purposes herein, slowing down or reducing the eye disease orcondition or the progression of the eye disease or condition is the sameas arrest, decrease, or reversal of the eye disease or condition.

The expression “effective amount” refers to an amount of an agent ormedicament, either in a single dose or as part of a series, which iseffective for treating or preventing an eye disease or condition orpredisposition thereto. This would include an amount that is effectivein achieving a reduction in one or more symptom as compared to baselineprior to administration of such amount as determined, e.g., by visualacuity or other testing. The effective amount will vary depending uponthe health and physical condition of the individual to be treated, thetaxonomic group of individual to be treated, the formulation of thecomposition, the assessment of the medical situation, and other relevantfactors. It is expected that the amount will fall in a relatively broadrange that can be determined through routine trials.

The terms “subject”, “patient” or “individual,” which are usedinterchangeably herein, refer to any subject, particularly a vertebratesubject, and even more particularly a mammalian subject, for whomtherapy or prophylaxis is desired. Suitable vertebrate animals that fallwithin the scope of the invention include, but are not restricted to,any member of the subphylum Chordata including humans, as well asnon-human primates, rodents (e.g., mice rats, guinea pigs), lagomorphs(e.g., rabbits, hares), bovines (e.g., cattle), ovines (e.g., sheep),caprines (e.g., goats), porcines (e.g., pigs), equines (e.g., horses),canines (e.g., dogs), felines (e.g., cats), avians (e.g., chickens,turkeys, ducks, geese, companion birds such as canaries, budgerigarsetc.), marine mammals (e.g., dolphins, whales), reptiles (snakes, frogs,lizards etc.), and fish. In specific embodiments, the “subject”,“patient” or “individual” is a human in need of treatment or prophylaxisof an eye disease or condition, including in subjects with a diabeticeye disease or condition or an ocular tumour. In specific embodiments,the terms “subject”, “patient” or “individual” refer to any single humansubject, including a patient, eligible for treatment who is experiencingor has experienced one or more signs, symptoms, or other indicators ofan eye disease or condition or predisposition thereto, whether, forexample, newly diagnosed or previously diagnosed and now experiencing arecurrence or relapse, or is at risk for an eye disease or condition, nomatter the cause. Intended to be included as a “subject”, “patient” or“individual” are any subjects involved in clinical research trials notshowing any clinical sign of disease, or subjects involved inepidemiological studies, or subjects once used as controls. The“subject”, “patient” or “individual” may have been previously treatedwith a medicament for an eye disease or condition, or not so treated.

The invention according to any above aspect may further comprise one ormore pharmaceutically acceptable carriers, diluents or excipients.

In a particular embodiment of any one of the above aspects, the compoundand compositions may be sterilized.

As used herein, glucocorticoid and mineralocorticoid includes atherapeutically active analog, derivative, pharmaceutically acceptablesalt, prodrug, metabolite or conjugate thereof.

As used herein, a derivative includes a therapeutically active orpharmaceutically active fragment of a compound modulating the activityof a mineralocorticoid receptor or a glucocorticoid receptor.

An analog may be a structural analog or a functional analog.

A homolog may comprise a molecule of the same chemical type, butdiffering by a fixed increment of an atom or a constant group of atoms.An example is methyl and ethyl alcohols which are homologous.

Table 1 below shows some example compounds and their measuredmineralocorticoid and glucocorticoid potencies.

In one embodiment, the compositions of the invention comprise asustained release composition. Based on the teachings herein, a skilledperson is readily able to select and/or formulate a suitable sustainedrelease composition.

In another embodiment, the compounds and compositions may be sterilised.From the teachings herein, a skilled person is readily able to select asuitable sterilisation method such as, heat treatment.

In another embodiment, the compositions of the invention arepreservative free.

In a particular embodiment, the compositions of the invention may becomprised in a syringe. In one embodiment, the syringe allows directinjection into an eye.

The inventors have also provided a pharmaceutical composition comprisingthe therapeutic agent described herein and optionally a pharmaceuticallyacceptable carrier, diluent or excipient.

By “pharmaceutically-acceptable carrier, diluent or excipient” is meanta solid or liquid filler, diluent or encapsulating substance that may besafely used in systemic administration. Depending upon the particularroute of administration, a variety of carriers, well known in the artmay be used. These carriers may be selected from a group includingsugars, starches, cellulose and its derivatives, malt, gelatine, talc,calcium sulfate, vegetable oils, synthetic oils, polyols, alginic acid,phosphate buffered solutions, emulsifiers, isotonic saline and salts,such as mineral acid salts including hydrochlorides, bromides andsulfates, organic acids such as acetates, propionates and malonates andpyrogen-free water.

The one or more pharmaceutically acceptable carriers, diluents orexcipients may comprise one or more of a wetting agent and a viscositymodifier.

A useful reference describing pharmaceutically acceptable carriers,diluents and excipients is Remington’s Pharmaceutical Sciences (MackPublishing Co. N.J. USA, 1991), which is incorporated herein byreference.

The above compositions may be administered in a manner compatible withthe dosage formulation, and in such amount as ispharmaceutically-effective. The dose administered to a patient, in thecontext of the present invention, should be sufficient to effect abeneficial response in a patient over an appropriate period of time. Thequantity of agent(s) to be administered may depend on the subject to betreated inclusive of the age, sex, weight and general health conditionthereof, factors that will depend on the judgement of the practitioner.

To allow injection, the composition may comprise a sufficientinjectability to be injected into an eye. By injectability is meant thatby pressing down on the plunger, the composition is injected into saideye in a controllable and consistent manner.

So that the invention may be readily understood and put into practicaleffect, the following non-limiting example is provided.

EXAMPLES Unit Dose Formulation

A unit dose formulation was prepared using two commercially availabletriamcinolone acetonide (TA) preparations. Both preparations areavailable from Farmabios SpA. One preparation has a particle size lessthan 10 µM, the other has a particle size of 10 to 40 µM with a mean of25 µM. The unit dose formulation comprised 0.1 ml of a 40 mg/ml solutionof TA amounting to 4 mg. The final unit dose formulation also comprised0.02 (w/v) polysorbate 80 and 0.6 (w/v) CMC. The 0.1 ml unit doseformulation was then added to a 0.5 ml, 27 gauge, glass syringe with apre-attached 1.2 mm needle.

Squeeze Test

A squeeze test to assess the ease of use of the 27 gauge needle may beconducted.

In Vitro Release Rate/Safety or Clinical Study

Studies of the in vitro release rate, along with a safety and/orclinical study may be conducted.

Aqueous Solubility and Enhancement of Drug Solubility Using Cyclodextrin

We have investigated the solubility enhancement of hydroxy-propylβ-cyclodextrin (HP-βCD) on the solubility of the MR compounds in saline,with a view to its potential use in the suspension formulations to boostthe amount of drug in solution.

FIG. 1 shows solubility enhancement for MR compounds and TA in salinewith addition of hydroxy propyl β-cyclodextrin (data are mean ± sd,n=3). Clearly, the solubility of FLU (fludrocortisone) and TA(triamcinolone acetonide) was enhanced >30 fold over the solubility insaline and increased linearly with cyclodextrin concentration in bothcases. The absolute solubility for TA is lower overall. In an aqueoussuspension formulation this would provide a much greater proportion ofdrug in solution at the time of administration, without the issues ofreduced activity. The increases in concentration for DCS(deoxycorticosterone acetate) were close to a linear relationship, andwas the greatest seen for all drugs, with the concentration in solutionwith 50 mM HP-βCD being >8 mg/mL. However, the concentrations for 11-DC(11-deoxycortisol) and DCSA (deoxycorticosterone acetate) plateau ataround 2 mg/mL. While the reason for this is not clear, the differencebetween the two sets of compounds is that FLU and TA were micronised,whilst DCS, DCSA and 11-DC were not, and the 48 hr mixing time may havebeen insufficient to attain full saturation of drug in saline. This isalso supported by the fact that DCS was closer to saturation as it has a4-8 fold greater solubility than 11-DC and DCSA. Given longer time toequilibrate, it would be anticipated that the solubility of 11-DC andDCSA would exceed 6 mg/mL, while that of DCS may in fact reach greaterthan 20 mg/mL based on the slope of the curve at low cyclodextrinconcentrations.

In all cases the use of hydroxypropyl hydroxy-propyl β-cyclodextrin(HP-βCD)-cyclodextrin should be considered to maximise the chance ofobserving a pharmacological effect with these poorly water solubledrugs.

Drug Storage Stability in Saline

To best ensure sterility of a final dose form, it was felt that aterminal sterilization approach in flame sealed glass ampoules would bethe preferred approach, yielding a ‘Kenalog’ style product, however thiswould necessitate the drug being in an aqueous salt environment forextended periods of time. Consequently it was felt to be important tocharacterise the drug stability over time in aqueous solution as anindicator of likely issues with drug content and/or degradation productsin the suspensions on storage. An accelerated stability trial wasconducted in which saturated drug solutions were prepared in saline (asa model for BSS) and samples were stored at 60° C. for up to 14 days.This was felt to reflect likely degradation profiles over at leasttwo-three months at ambient/refrigerated temperatures. Triplicatesamples were removed from the oven at 1, 3, 7 and 14 days and analysedfor drug content to follow loss of active, and the appearance of peaksin the spectrum. (A dedicated diode array detector is used with the HPLCfor these studies as a powerful tool in identifying that compounds areproduced that may not absorb at 240 nm and hence would not appear as‘peaks’ in the single wavelength chromatogram).

The profiles for drug concentration over time are presented in FIG. 2for each drug. It is apparent that 11-DC is stable over a week, andslightly declined in the second week, but was still at aconcentration >90% of that originally in the sample. Fludrocortisonedisplayed marked instability, declining to only 20% of the originalconcentration after two weeks. The remaining drugs were essentiallystable over the test period. Some variability in results was evident forDCSA and TA, which we have attributed to their very low aqueoussolubilities relative to the other compounds. The instability offludrocortisone, in particular, may exclude the use of pre-packagedaqueous suspensions as a suitable dose form, at least forfludrocortisone, due to the likely production of high levels ofdegradation products and other avenues need to be pursued.

Drug Stability Under Sterilization Conditions (Autoclave and GammaIrradiation) Drug Aqueous Solutions

Preferably, the study materials are sterile, at least to a large degreefor preclinical studies. In the absence of a facility for completeaseptic manufacture, in order to sterilize the suspensions there are twopossible approaches foreseen - autoclaving the final suspensions ‘invial’, or gamma sterilization. Consequently, in order to initially testthe resistance of the drug to degradation in the ‘wet’ environment, drugin saturated solutions were prepared as for the storage stabilitystudies above and subjected to autoclave conditions (121° C./30 min) orgamma irradiation (~25 kGy at ambient temperature).

Gamma irradiation was conducted at a firm in Melbourne (Steritech; 160South Gippsland Hwy, Dandenong Sth) and QC certificates providedverifying dose of gamma irradiation received. The samples were exposedto 25 kGy radiation, which severely discoloured the vials, in long termthis method may be very suitable when an appropriate glass container,resistant to gamma rays, is used for sample preparation.

From FIG. 3 it is apparent that 11-DC and DSC were stable to autoclaveconditions. TA was moderately stable but this was still felt to bepossibly unacceptable degradation of the active under these conditions.FLU was also partly degraded to a similar or worse level as TA, whileDCSA was completely degraded. Gamma irradiation had a devastating effecton drug concentration with virtually no drug remaining intact for any ofthe solutions except 11-DC where less than 20% of the initial drugcontent remained after sterilization.

The use of a diode array detector allows some interpretation of what isoccurring in the samples based on the 3-dimensional absorbance versuswavelength versus retention time plots. In particular, FIG. 4 belowindicates that DCSA has been completely degraded to DCS under autoclaveconditions, but was completely degraded under gamma irradiation, i.e. noDCS or DCSA were evident in the 3D-contour plot. The degradation of DCSAto DCS is important, as it is necessary to be certain that thepharmacological response in the in vivo studies is due to DCSA and notDCS produced by drug degradation in solution.

Drug Powders

The poor stability of most drugs under either autoclave or gammairradiation when in contact with aqueous diluent led to a further set ofstability studies to test the effect of gamma irradiation on the drydrug powders, with a view to providing the study materials as sterilepowders for reconstitution immediately prior to administration.

FIG. 5 demonstrates the stability of the powders when subjected to gammasterilization and assayed for subsequent drug content compared to asimilarly handled, non-irradiated control. Only DCSA appeared todemonstrate a slight reduction in drug content, however only one samplewas analysed so the difference may be due to inevitable slightsystematic error, but is still remarkably high when compared to the datain FIG. 3 .

Particle Size and Refinement

It is recommended in the literature that particle size of ocularsuspensions should be less than 50 microns and preferably less than 25microns to avoid irritation to ocular tissues from large crystals ofdrug. The triamcinolone acetonide and fludrocortisone used in thesestudies were micronised powders directly from Farmabios; however, theremaining three drugs were obtained from Sigma Alrich as commercialsamples that were not micronised. Hence it was of importance to: (i)Characterize the size of the remaining three powders and to confirm thatof TA and FLU before proceeding; and (ii) to refine the particle sizewhere required to obtain appropriate sized material to progress to studymaterial development.

Particle Sizing by Laser Light Scattering

Table 2 shows the measured particle size distribution for ‘as received’samples of powdered compounds. It is clear that the three non-micronisedsamples would need further refinement in order to make it suitable forformulation into an injectable intravitreal product.

SEM Imaging of Raw Materials

The powders were investigated also by SEM for morphology, aggregation orother phenomena that may not be apparent in laser light scattering. Therepresentative images shown in FIG. 6 agree well with the particlesizing results in the previous section.

It is clear that all three non-micronised powders require refinement tomake them suitable for formulation for back of eye applications. Itbecame apparent that with the small quantities of the powders available,the regular methods of ball milling or jet milling would be unlikely toyield adequate results, and very low yields of powder would likelyeventuate. It was decided that wet milling with a homogenizer would bethe best approach, and a homogeniser was used for the purpose(Polytron).

Samples of 11-DC, DCS and DCSA were prepared as suspensions with 0.4%Tween 80 (also known as Polysorbate 80) as a wetting agent, andhomogenised with a Polytron on speed 6 for varying amounts of time todetermine the required processing time. As can be seen in the individualplots below in FIG. 7 , the process was effective for all drugs. Atarget D(v,0.9), which indicates the size below which 90% of theparticles are represented, was set at 20 micron, and in all cases thiswas achieved in 20 mins or less processing time, and consequently thismethod was used for particle refinement for the rest of the formulationdevelopment tasks.

Formulation Manufacture Development and Process Optimization

The following intermediate conclusions were adopted in deciding on thefinal formulation approach. 1. Autoclave and gamma sterilization are notsuitable sterilization methods for these compounds when in aqueous form.2. Gamma sterilization appears to be suitable for powders when in dryform only. 3. The particle size of 11-DC, DCS and DCSA needs to berefined by wet milling to be adequate for these studies.

Thus a broad approach was adopted involving the following stages: Wetsieve drugs Particles to D (V, 0.9) less than 20 µM; Freeze Dry DrugAlone; Add solution of all excipients to drug powder in tube; dispenseto vials and freeze dry; gamma sterilize and quality control;reconstitute in BSS at time of study or use.

From Table 3, our conclusion was that all drugs apart of TA without CMCand Tween80 experienced suspendability problems therefore therecommended formulation includes CMC and Tween 80 as shown in Tables 3and 4.

Consequently, the formulation of Table 4 was utilized for the studymaterials.

Summary of Batch Production Results Indicating Applicability of Method

Table 5 shows a summary of batch production results. The one failedresult had a dose of DCSA in the vial slightly below the lowerspecification of 18 mg. This is likely due to slight degradation of theactive during gamma sterilization, but did not give rise to unidentifiedpeaks in the HPLC chromatograms.

Triesence Composition

Table 6 shows the composition of Triesence as listed directly on theProduct Information sheet. Accordingly, one option is to use the aboveprocess and the Triesence formulation to prepare fludrocortisone systemfor reconstitution.

Kenalog Composition

Table 7 shows the composition of Kenalog as listed directly on theProduct Information sheet. At the time of manufacture, the air in thecontainer is replaced by nitrogen. Sourced fromhttp://packageinserts.bms.com/pi/pi_kenalog-10.pdf.

A Phase Ib, Study of Safety and Tolerability of IntravitrealFludrocortisone Acetate (FCA) and Triamcinolone (TA)

Investigational Product, Dose and Route of Administration:Fludrocortisone acetate (FCA) 1 mg/0.1 ml & 2 mg/0.1 ml, Intravitreal(IVT) injection. The identical protocol will be followed with TA.

Rationale for dose: Single dose of 0.1 ml in a concentration of 1 mg/0.1mL and 2 mg/0.1 mL was selected based on a previous pre-clinical model.There were no signs of retinal toxicity on slit- lamp examination,indirect ophthalmoscopy, or by light microscopy in all eyes injectedwith 400 µg/0.1 mL, 1 mg/0.1 mL and 2 mg/0.1 mL. However, it wasreported 1 case of intravitreal haemorrhage in 4 mg/0.1 mL.

Systemic injection of fludrocortisone acetate has serious mineralcorticoid and glucocorticoid side effects such as hypertension,potassium loss, Cushingoid changes, etc. Intravitreal injectionfludrocortisone acetate may avoid systemic side effects.

Objectives: To determine safety and tolerability of a single dose IVTinjection of 1 mg/0.1 mL and 2 mg/0.1 mL FCA.

Study Population: The study is planned to enrol up to 9 participants.

Study Design: This study is planned to enrol 9 participants to assessdose escalation based on a 3+3 algorithm. Enrolment will stop if > 2patients experience dose-limiting toxicity at any time during the study.Dose-limiting toxicity is defined by intraocular inflammation, elevatedIOP (intraocular pressure), reduced vision (loss of≥15 letters), orhaemorrhage within 28 days after injection.

Part 1 involves a single participant to assess safety and tolerabilityof 1 mg/0.1 mL FCA. This participant will be followed for up to 28 daysand reviewed by a safety review committee prior to the recruitment of afurther 2 participants treated with 1 mg/0.1 mL FCA totalling in 3participants in the first cohort.

Part 2 involves a single participant to assess safety and tolerabilityof 2 mg/0.1 mL FCA. This participant will be followed for up to 28 daysand reviewed by an independent safety review committee prior to therecruitment of a further 5 participants treated with 2 mg/0.1 mL FCAtotalling in 6 participants in the second cohort.

The sample size (n=9) chosen for this study was selected without formalstatistical justification, but the numbers chosen are consideredadequate for assessing the study objectives. The sample size wasdetermined on the basis of practical and logistical considerations for apilot study, and not based on statistical power with regard tohypothesis testing or precision with regard to parameter estimation.

Description of Study Intervention: Fludrocortisone acetate(9-α-Fiuoro-11β. 17α, 21-trihydroxy-4-pregnene-3, 20 dione acetate) is asynthetic steroid possessing a potent mineralocorticoid effect and ahigh glucocorticoid activity. The physiologic effects of fludrocortisoneacetate are similar to hydrocortisone but much more potent. FCA has aglucocorticoid activity ten times higher than cortisol and amineralocorticoid effect 250 times higher than cortisol. Addition offluorine to C-9 of cortisol gives fludrocortisone a markedly increase inglucocorticoid, mineralocorticoid and anti-inflammatory potency. Thedrug will be administered via intravitreal injection.

Study Duration: 6-months’ recruitment and 6-month follow-up period.

Participant Duration: Participants will be on the study for 6 months.Screening: up to 14 days Treatment: 1 day. Follow-up: 6 months.

Pharmacokinetic (PK) parameters: Exposure after single doseFludrocortisone acetate IVT injections; Serum maximum observedconcentration; Time to maximum measured concentration; Terminalelimination half-life.

Planned Interim Analysis: There is no formal interim analysis plannedfor this study. However, a data safety monitoring board (DSMB) forsafety data review will be planned for this study.

Analysis Populations - the following analysis populations are planned:Safety Population: all enrolled participants IVT Fludrocortisone acetatewill be included in the safety population; intention-to-treat (ITT)Population: all enrolled participants who received IVT Fludrocortisoneacetate and had at least one efficacy measurement taken after dosingwill be included in the ITT population.

Statistics Analyses- Safety Analysis: Statistical methods for the safetyanalyses will be primarily descriptive in nature. Listings and summariesfor all safety data will be presented using the Safety Population.Descriptive statistics (mean, SD, median, minimum and maximum) will becalculated for summaries of continuous safety data and frequency countsand percentages (where appropriate) will be calculated for summaries ofdiscrete/categorical safety data. Safety data, including vital signs,clinical safety labs and adverse events, will be summarised. Change frombaseline will be included in summary tables for vital signs andlaboratory parameters. All laboratory data will be included in the datalistings and all test values outside the normal range will be flagged.Physical examinations will be listed for each participant. Adverseevents (AEs) will be coded using the Medical Dictionary for RegulatoryActivities (MedDRA), and data will be summarised by System Organ Classand preferred term.

Categorical efficacy endpoints such as slit lamp biomicroscopy examfindings, dilated ophthalmoscopy exam findings, colour fundusphotography and OCT findings will be summarised descriptively byfrequency count and percentage (proportion) as appropriate.

Schedule of Activities: this is summarised in Table. 8.

Formulation:

The formulation is manufactured using aseptic processes. It is packagedin glass vials with coated rubber stoppers with plastic flip-off disksand are to be used for single-dose administration only. Part A: 10 mg ofFludrocortisone will be placed in a vial which will be sent off forGamma Sterilization. Part B: Will be a vial containing the sterilediluent. These processes will be carried out by a trained Pharmacist andSterile Facility technician in a Grade B Room under a Grade A hood. Theinvestigational product will be produced by an accredited compoundingpharmacy under GMP.

Storage and Handling:

Fludrocortisone is formulated for intravitreal administration as a 10 mgpowder for solution for injection.

Each vial contains 10 mg of fludrocortisone powder. The diluent consistsof Isotonic Sterile Saline (Sodium Chloride solution 0.9%). Thefludrocortisone powder for solution for intravitreal injection isreconstituted with 1.0 ml or 0.5 ml of diluent for injection dependingon the concentration required. Following reconstitution, theconcentration is suitable for delivering at a 1 mg/0.1 ml or 2 mg/0.1 mldose in 0.1 ml intravitreal injection volume.

The fludrocortisone 10 mg powder for solution and diluent is for singleuse and must be stored at 2-8° C., protected from light.

Pharmaceutical Form:

Fludrocortisone is formulated for intravitreal administration as a 10 mgpowder for solution for injection.

Each vial contains 10 mg of fludrocortisone powder. The diluent consistsof Isotonic Sterile Saline (Sodium Chloride solution 0.9%). Thefludrocortisone powder for solution for intravitreal injection isreconstituted with 1.0 ml or 0.5 ml of diluent for injection dependingon the concentration required. Following reconstitution, theconcentration is suitable for delivering at a 1 mg/0.1 ml or 2 mg/0.1 mldose in 0.1 ml intravitreal injection volume.

The fludrocortisone 10 mg powder for solution and diluent is for singleuse and must be stored at 2-8° C., protected from light.

Dosage and Administration:

Fludrocortisone may be provided as single-use stoppered glass vialscontaining sterile fludrocortisone 50 mg. Dry powder fludrocortisonediluted in sterile saline has been injected into one patient. 50 mgsterilised dry powder fludrocortisone was diluted by added 5 ml sterilesaline into the vial containing the fludrocortisone. 0.1 ml was injectedinto any eye.

The indicated IVT dose of fludrocortisone will be administered by oneintravitreal injection of up to 0.1 ml of 1 mg/0.1 ml and 2 mg/0.1 mlfludrocortisone.

Intravitreal Toxicology:

Intravitreal doses of Fludrocortisone acetate of 0 (vehicle control),400 µg, 1 mg, 2 mg, 4 mg/eye were tested in a study of New Zealandalbino rabbits.

All animals were examined before and after injection using the indirectophthalmoscope and slit-lamp biomicroscopy. Electroretinography (ERG)was performed on all animals before intravitreal injection and two weeksafter injection. The animals were re-examined at this time by indirectophthalmoscopy and slit-lamp biomicroscopy and were euthanized. The eyeswere enucleated and examined with light microscopy.

One eye in the 4 mg/0.1 ml fludrocortisone group exhibited significantdecreases in ERG; one eye of this group had a vitreous hemorrhage. Therewas no significant decrease in ERG in the other groups. There were nosigns of retinal toxicity on slit-lamp examination, indirectophthalmoscopy, or by light microscopy in all eyes injected with 4mg/0.1 ml or less of fludrocortisone. Intravitreal injections offludrocortisone at 2 mg/0.1 ml appeared safe in albino rabbit eyes.

Animal Studies

An animal study was conducted to evaluate the safety and efficiency ofFludrocortisone acetate after intravitreal injection into the vitreouscavity [see Kivilcim, M., et al., Evaluation of the Retinal Toxicity ofFludrocortisone Acetate After Intravitreal Injection. InvestigativeOphthalmology & Visual Science, 2006. 47(13): p. 4281-4281]. Surgerieswere performed on the eyes of 25 New Zealand white rabbits.Fludrocortisone acetate was titrated using sterile BSS solution to thefollowing concentrations: 4 mg/ 0.1 ml, 2 mg/ 0.1 ml, 1 mg/0.1 ml, and400 µg/0.1 ml, which were injected intravitreal into one eye oftwenty-five rabbit eyes. The control eyes received 0.1 ml of sterileBSS. All animals were examined before and after injection using indirectophthalmoscope and slit-lamp biomicroscopy. Electroretinography (ERG)was performed on all animals prior to intravitreal injection and twoweeks after injection. The animals were re-examined at this time byindirect ophthalmoscope and slit-lamp biomicroscopy and were euthanized.Their eyes were enucleated and examined with light microscopy.

Outcomes from these in vivo tests were positive for the application ofintravitreal fludrocortisone acetate. In multiple measurements, up to 40days of observations, the slit lamp biomicroscopy and indirectophthalmoscopy did not show any evidence of significant inflammation inthe anterior or posterior segment of the eye in either the control ortreatment groups. IOP was normal across all groups.

Histological examination of retinal sections, under light microscopy,revealed that the integrity of the retinal layers appeared preservedwith no evidence of toxicity or vacuolization except for one eye in the4 mg group. All aggregates of fludrocortisone acetate disappeared by 22+/-8 days in the 2-mg group, and 33 +/-7 days in the 4-mg group.

In ERG testing, one eye injected with 4 mg/0.1 ml exhibited decreases inERG output. All other eyes had a normal ERG. These findings representpromising results for intravitreal Fludrocortisone acetate that isclinically suitable for both short-term and long-term use.

Rationale Rationale for This Study:

Fludrocortisone acetate is available in tablet form (0.1 mg) from thePBS and so is approved for use in humans in Australia. In a study of 121patients, excellent outcomes with fludrocortisone for anterior segmentlesions were reported (see Gonzalez, C., Topical fludrocortisone(9-alpha fluorohydrocortisone) in ophthalmology. Am J Ophthalmol, 1960.49: p. 619-22). This document cited 4 previous papers with similarexperiences.

There is older pre-clinical data suggesting FCA is effective. Among thatis Fitzgerald et al. who found that FCA was superior to TA in a study ofphorbol-12-myristate- acetate (PMA)-stimulated monkey choroidalendothelial cells (CECs) in restoring quiescent morphology and reducingmembrane permeability (Fitzgerald, M., et al., Mineralocorticoidsrestore quiescent morphology and reduce VEGF receptor expression ininflamed choroidal endothelial cells in vitro. Ophthalmic Res, 2009.41(1): p. 44-52). Prof Jan Provis et al. have a large body of newpreclinical data that indicates FCA is superior to TA in a rat model ofdry AMD. FCA was superior in terms of preventing cell death, macrophagerecruitment, and preserving a- and b-wave ERG amplitude.

Kivilcim cited above, examined intravitreal FCA in 25 normal rabbits at4 mg/0.1 ml, 2 mg/0.1 ml, 1 mg/0.1 ml, and 400 µg/0.1 ml. Two eyes at 4mg/0.1 ml experienced intravitreal haemorrhage and reduced ERG. Therewere no other problems of reductions in ERG. The smaller volume of therabbit eye would suggest 4 mg/0.1 ml would be safe in humans. TA iscommonly given at 4 mg/0.1 ml so comparing the same doses for eachsteroid would be sensible.

Dose Selection:

A single dose of 1 mg/0.1 mL or 2 mg/0.1 mL injection administered oncewill be tested in this study.

Intravitreal fludrocortisone acetate was well-tolerated in a panel ofanimal toxicology studies. The volume of the human vitreous isapproximately 4 mL, which is approximately 2.7-fold larger than the meanvitreous volume of rabbits, 1.5 mL. Based on the difference in vitreousvolume between man and rabbit, the human equivalent dose was determinedto be 67 mg/eye every 4 weeks. The dose (1- or 2 mg/0.1 mL injection) offludrocortisone acetate that will be evaluated in this clinical study isexpected to result in drug concentrations approximately 1.3 fold lowerthan observed in rabbits.

Risk/Benefit:

The safety monitoring practices employed by this protocol (e.g. completeophthalmologic exam, IOP monitoring, OCT, vital signs, hematology, serumchemistry, and AE questioning) are adequate to protect the subjects’safety.

There are risks associated with the ophthalmic procedures required forparticipants in this study. However, these are all standard proceduresthat are widely performed in ophthalmology.

In the days following any IVT injection, patients are at risk ofdeveloping endophthalmitis. If the eye should become red, sensitive tolight, painful, or develop a change in vision, the patient will beinstructed to seek immediate care from an ophthalmologist. Other risksof IVT injection include traumatic cataract, retinal detachment andhemorrhage.

Transient increased IOP has also been identified as a risk following IVTinjections. IOP will be carefully monitored in this study.

The approximately 150 mL of blood planned for collection from eachsubject over the 6 months of the study does not pose an undue risk inthis patient population.

Based on data available to date, IVT administration of fludrocortisoneacetate does not seem to present an unreasonable ophthalmic or systemicrisk in animal models. Fludrocortisone acetate has been safely usedsystemically as mineralocorticoid replacement for severe orthostatichypotension in Addison’s disease and other salt- water disbalances.

However, as fludrocortisone acetate has not been used intravitreally inhuman participants there are potential unforeseen risks. To mitigatesuch risks, this study is being conducted in two parts, restrictingtreatment to a single individual together with extended assessment,prior to application in other participants. Numerous follow-up visitsand numbers of testing procedures have also been instituted in theassessment schedule for all participants to ensure adverse events, orother safety issues that arise are identified and addressed in a timelymanner.

There is a potential health benefit for trial participants from receiptof study drug. We propose to administer intravitreal fludrocortisoneacetate. If efficacious, intravitreal fludrocortisone acetate isexpected to alter the course eye disease and slow its rate ofprogression.

Objectives and Endpoints Study Objectives:

The primary objectives of the study are to assess the safety andtolerability of IVT injections of Fludrocortisone acetate in order tosupport further development into confirmatory Phase II studies.

Study Endpoints Primary Safety Endpoint:

To demonstrate safety and tolerability of IVT injections ofFludrocortisone acetate number and severity of local and systemictreatment emergent adverse events.

Secondary Endpoints:

Change in best corrected visual acuity (BCVA) Change in low luminancebest corrected visual acuity (LL-BCVA). Change in vital signs. Increasein IOP. Pharmacokinetic (PK) parameters. Exposure after single dosefludrocortisone acetate IVT injections. Serum maximum observedconcentration. Time to maximum measured concentration. Terminalelimination half-life.

Study Population

The study population includes approximately 9 (n=9) subjects to beenrolled at approximately one (1) site. If both eyes have the samevisual acuity, the right eye will be used as the study eye.

The complete inclusion and exclusion criteria are presented above.

Women of Childbearing Potential (WOCBP)

WOCBP are defined as pre-menopausal women physiologically capable ofbecoming pregnant.

Women of Non-Childbeari Ng Potential

WONCBP are defined as women meeting any of the following criteria: Olderthan 45 years with amenorrhea for > 2 years or older than 60 years withamenorrhea for > 1 year, both confirmed by FSH and LH levels; Hasundergone hysterectomy; Has undergone bilateral oophorectomy; and Hasundergone bilateral salpingectomy.

Approved Methods of Contraception

Approved methods of contraception include: oral contraceptives,intrauterine device, medically acceptable barrier methods (i.e. condom),implantable or injectable contraceptives or removable birth controldevice. Subjects practicing abstinence and coitus interruptus (pull outmethod) must agree to use an approved method of contraception during thestudy

Treatment of Subjects Allocation of Treatment:

Each subject will be assigned a unique screening number beforescreening. Subjects who complete the study screening assessments andmeet all the eligibility criteria will be scheduled to enter the studyand will receive treatment with intravitreal fludrocortisone acetate onDay 0.

Treatments Administered Dose Levels and Study Arms:

A single dose of 1- and 2 mg Fludrocortisone acetate/0.1 mL will betested in this study.

Subjects will receive 1 IVT injection as outlined in Table 9.

Drug Supplies Identity of Investigational Product

Fludrocortisone acetate is formulated for intravitreal administration asa 50 mg powder for solution for injection.

Each vial contains 50 mg of fludrocortisone powder. The diluent consistsof Sodium Chloride solution (0.9%) quantity sufficient to 100%. Thefludrocortisone powder for solution for intravitreal injection isreconstituted with 1.0 ml and 0.5 ml diluent for injection dependentupon concentration required. Following reconstitution, the concentrationis suitable for delivering at a 1 mg/0.1 ml or 2 mg/0.1 ml dose in 0.1ml intravitreal injection volume.

The fludrocortisone acetate 50 mg powder for solution and diluent is forsingle use and must be stored at 2 to 8° C., protected from light.

Accountability

IVT Fludrocortisone acetate drug product will be provided to a designeeat the study site and must be stored in a pharmacy or otherwise lockedand secured, at temperatures between 2° C. and 8° C. in a refrigeratedarea with limited, controlled access and temperature monitoring; do notfreeze. IVT Fludrocortisone acetate drug should be protected from lightby storing in the carton provided. The drug product supply is accessibleonly to those individuals authorized by the PI. The Sponsor will supplysufficient quantities of fludrocortisone acetate drug product to allowcompletion of this study.

Designated study staff will provide the study treatments to the subjectsin accordance with their assigned subject numbers and the randomizationschedule. During the study, the receipt of the drugs supplied at theclinical site and of study treatment dispensation for each subject willbe documented in drug accountability records. These drug accountabilityrecords are to be kept separate from the patient medical records andother source documents.

All used vials should be retained by the clinical site until drugaccountability monitoring is performed and then returned to the Sponsoror designee, or destroyed per Sponsor instructions.

At the conclusion of the study, any unused investigational product willbe retained by the clinical site, returned to the Sponsor or designee,or destroyed per Sponsor instructions, and this will be documented inthe drug accountability records.

Intravitreal Fludrocortisone Acetate Administration

Subjects receiving active treatment will be administered a 1 mg/0.1 mlor 2 mg/0.1 mL IVT injection of Fludrocortisone acetate using a 27 Gthin wall needle, at the discretion of the PI.

Clinic staff involved in the injection tray assembly, anaestheticpreparation, and study drug preparation and administration will followappropriate aseptic techniques to minimize the risk of potential adverseevents associated with IVT injections (e.g. endophthalmitis).

The investigation drug will be presented in a kit containing 1 × 1 mlsyringe with 27 g 12 mm needle, 1 × 5 ml vial containing sterilefludrocortisone 10 mg, 1 × Vial containing 2 ml Diluent forreconstitution and alcohol swab to swab top of vials before puncturingbungs.

Preparation of the solution: The injecting doctor will withdraw 1.0 mlor 0.5 ml of diluent and reconstitute the powder. The doctor will thendraw up 0.1 ml of the fluid ready for injection.

To minimize IOP elevation after IVT injection of fludrocortisoneacetate, decompression of the eye must be performed before allfludrocortisone acetate injections. This is done by applying moderatepressure to the globe with cotton swabs for 30-60 seconds duringaesthetic preparation.

In addition to the procedures outlined in this protocol, adherence tospecific institutional policies associated with IVT injections will beobserved.

Concomitant Therapies

Any concomitant medications a participant is receiving at the start ofthe study or that are given for any reason during the study (except forroutine medications given for ocular procedures required by theprotocol, such as topical aesthetic) must be recorded in the sourcedocument and CRF including start and stop date and time, dose, route,and indication. In addition, all ocular and non-ocular procedures suchas surgical procedures (excluding study treatment procedures) must alsobe recorded in the source document including start and stop dates.Surgical anaesthetics, paramedical or alternative therapies (e.g.acupuncture, massage) should also be recorded in the source documentsand CRF. Metoclopramide or other agents to prevent nausea induced byfluorescein injection may be administered at the discretion of the PI.

Endophthalmitis Treatment

The decision to treat a participant for endophthalmitis or suspectedendophthalmitis will be guided by the clinical judgment of the PI. Thetreatment method (pars plana vitrectomy vs. vitreous tap) and choice ofantimicrobial agents are also at the discretion of the PI and shouldfollow current standard practice patterns. The decision to use IVTsteroids (e.g. dexamethasone) for the treatment of endophthalmitis isalso at the discretion of the PI.

Study Procedures Study Design:

This is a Phase Ib study to assess the safety and tolerability of asingle dose of IVT injection of fludrocortisone acetate.

The study is planned to enroll an initial cohort of 3 patients in a doseof 1 mg/0.1 mL. A total of 9 participants can be included to assess doseescalation based on 3+3 algorithm.

Patients should be screened up to 14 days before receivingFludrocortisone acetate. Upon entry into the study, patients will beassigned a subject screening number. Subjects who meet all inclusion andexclusion criteria and are confirmed as eligible by the CRC will returnto the clinic for the administration of single dose IVT Fludrocortisoneacetate (Day 0) as outlined below.

All subjects will return to the clinical site on Day 1 and Day 7 toassess acute safety after the injection. After that, all subjects willreturn for another 6 follow-up visits and 6 months after the injection.See Study Outline below.

Safety will be assessed throughout the study; serial blood samples andurine samples will be collected. Blood samples will also be collectedfor the PK assessment of fludrocortisone acetate.

The planned length of participation in the study for each subject isapproximately 6 months (from Day 0 - through completion of the Month 6(Day 150) follow-up procedures).

The study is planned to take place over approximately 12 months (fromscreening of the first subject through completion of the last subject’sexit visit).

Subject Enrollment

It is the responsibility of the investigator to ensure that subjects areeligible to participate in the study prior to enrollment and throughoutthe study. Documentation of the personally signed and dated informedconsent of each subject, using the study-specific ICF, is requiredbefore initiating the Screening process. After written informed consenthas been obtained and eligibility to participate established,investigative site personnel will obtain the subject’s identificationnumber. Only eligible subjects will be allocated to the open label FCA 1mg/0.1 mL or 2 mg/0.1 mL.

Enrolment will occur in two parts in order in order to minimise thelikelihood that subjects will be exposed to risks. During part 1 & 2,subjects will be screened one by one as only one patient will initiallybe enrolled during part 1 of the trial. The first enrolled subject willparticipate in a screening period of up to 14 days and a follow-upperiod of 28 days, to detect an IOP response.

After the first subject has completed the follow-up of 28 days after FCA1 mg/0.1 mL injection, The subject’s safety data will be reviewed thesafety data of this will be reviewed by an independent safety reviewcommittee to determine whether to commence enrolment of additional 2patients in the first cohort of 1 mg/0.1 mL dose of FCA. Enrolment willbe stopped if >2 patients experience limiting-toxicity adverse eventrelated to the study drug. If no more than two adverse events consideredto be related to the study drug occur with limiting toxicity, the secondcohort will be recruited. Dose-limiting toxicity is defined byintraocular inflammation, elevated IOP, reduced vision (loss of≥15letters), or haemorrhage within 28 days after injection.

Part 2 will take in place if the 3 subjects have tolerated well thedose. Part 2 initially involves a single subject treated with 2 mg/0.1mL FCA to assess safety and tolerability. This subject will be followedfor up to 28 days and reviewed by an independent safety review committeeprior to the recruitment of a further 5 subjects treated with 2 mg/0.1mL FCA totalling in 6 subjects in the second cohort.

Meeting minutes will be generated at each meeting and included in thesponsor’s study files. Formal reports will not be prepared prior to orfollowing these meetings. As general guidance, a subject will beconsidered to have tolerated a dose if the subject experiences noclinically significant drug-related adverse event or laboratoryabnormality. Conversely, a subject will not be considered to havetolerated the dose if he experiences a clinically significantdrug-related adverse event or laboratory abnormality during the studydrug administration or post-administration follow-up period

Safety to cataract will be reviewed among all participants at the 150day review.

It is understood that safety is a medical judgment that cannot beprospectively defined in detail. Subjects will be closely monitored withclinical observations and safety laboratory testing.

Study Visit Schedule

Below is a condensed description of the study visits and the proceduresand examinations that will be performed. Please refer to the Schedule ofActivities (SoA) table for a detailed schedule of procedures/assessmentsfor the Monthly visit schedules. Additional safety assessments notlisted herein may be performed if considered necessary at the discretionof the PI.

Screening - Within 14 Days Prior to Treatment

Visit 1 - All Subjects: All ophthalmic procedures (including imaging)are to be performed on both eyes:

1. Before any study specific procedures are performed, explain thepurpose and nature of the study, and have the patient read, sign, anddate the Institutional Review Board/Independent Ethics Committee(IRB/IEC) - approved Informed Consent Form (ICF). Have the individualobtaining consent from the patient and a witness, if applicable, signand date the ICF. 2. Obtain a screening number for the subject. 3.Obtain information on demographics, medical/ocular history, andconcomitant medications used 90 days prior to enrolment. Includevitamins, and all over-the-counter as well as prescription medications.4. Screen the patient for inclusion/exclusion criteria. 5. Collect blood(including blood for HCG/FSH/LH, if applicable) and urine for laboratoryanalysis and forward the samples to the central laboratory. 6. Collectvital signs. 7. Perform BCVA. 8. Perform LL-BCVA. 9. Perform a completeophthalmic exam including slit-lamp exam of the cornea, iris, anteriorchamber, lens (LOCS III if any opacity on the lens noted) and aqueousreaction (cells and flare), dilated fundus exam of the vitreous andretina and IOP measurement. 10. Perform SD-OCT imaging for determinationof eligibility by the PI. 11. Perform FAF imaging for determination ofeligibility by the PI. 12. Perform NIFR imaging. 13. Perform DCFP fordetermination of eligibility by the PI. 14. Perform FA for determinationof eligibility by the PI.

Visit 2 (Baseline) - All subjects: Unless specified, all ophthalmicprocedures (including imaging) are to be performed on the Study eyeonly. 1. Verify that all inclusion/exclusion criteria are met, includingthe determination of eligibility by the PI. 2. Obtain information on anychanges in medical health and/or the use of concomitant medications. 3.Collect vital signs pre- and post-dose. Vital signs will be measuredwithin 1 hour prior to dosing for the pre-dose time point. Post-dosevital signs readings will be performed within 30 minutes after dosing.4. Perform BCVA. 5. Perform LL-BCVA. 6. Perform a complete ophthalmicexam including slit-lamp exam of the cornea, iris, anterior chamber,lens (LOCS III if any opacity on the lens noted) and aqueous reaction(cells and flare), dilated fundus exam of the vitreous and retina andIOP measurement. 7. Perform the IVT injection of fludrocortisoneacetate. 8. Monitor the study eye within 15 minutes’ post injection. 9.Monitor for adverse events.

Visit 3 (Day 1): All Subjects. Post-initial treatment examination:

Unless specified, all ophthalmic procedures (including imaging) are tobe performed on the study eye only. 1. Obtain information on any changesin medical health and/or the use of concomitant medications. 2. Collectvital signs. 3. Perform BCVA. 4. Perform LL-BCVA. 5. Perform a completeophthalmic exam including slit-lamp exam of the cornea, iris, anteriorchamber, lens (LOCS III if any opacity on the lens noted) and aqueousreaction (cells and flare), dilated fundus exam of the vitreous andretina and IOP measurement.

Monitor for Adverse Events:

Follow-up Visits - Day 7, 14, 28, 60, 90: Unless specified, allophthalmic procedures (including imaging) are to be performed on thestudy eye only. The following procedures will be performed at allfollow-up visits: 1. Obtain information on any changes in medical healthand/or the use of concomitant medications. 2. Collect vital signs 3.Collect blood for PK analysis (days 7, 28 and 90 only). 4. Perform acomplete ophthalmic exam including slit-lamp exam of the cornea, iris,anterior chamber, lens (LOCS III if any opacity on the lens noted) andaqueous reaction (cells and flare), dilated fundus exam of the vitreousand retina and IOP measurement. 5. Monitor for adverse eventsTermination Visit (or Early Termination) - Day 150: All ophthalmicprocedures are to be performed on BOTH EYES. 1. Obtain information onany changes in medical health and/or the use of concomitant medications.2. Collect blood and urine for laboratory analysis and forward thesamples to the central laboratory. 3. Collect blood for PK analysis. 4.Collect vital signs. 5. Perform urine pregnancy test. -WOCBP only.

6. Perform BCVA. 7. Perform a complete ophthalmic exam includingslit-lamp exam of the cornea, iris, anterior chamber, lens (LOCS III ifany opacity on the lens noted) and aqueous reaction (cells and flare),dilated fundus exam of the vitreous and retina and IOP measurement. 7.Perform SD-OCT imaging. 8. Perform FAF imaging. 9. Perform NIFR imaging.10. Perform DCFP. 11. Perform FA imaging. 12. Monitor for adverse events

Unscheduled Visit:

If a subject return to the clinical site before their next scheduledvisit for an assessment of an adverse event or at the request of the PI,all assessments completed at the Unscheduled Visit should be documentedin the patient source record and in the eCRF.

Lost to Follow-Up

A participant will be considered lost to follow-up if he or she fails toreturn for ≥1 scheduled visits and is unable to be contacted by thestudy site staff.

The following actions must be taken if a participant fails to return tothe clinic for a required study visit:

The site will attempt to contact the participant and reschedule themissed visit within one week and counsel the participant on theimportance of maintaining the assigned visit schedule and ascertain ifthe participant wishes to and/or should continue in the study.

Before a participant is deemed lost to follow-up, the investigator ordesignee will make every effort to regain contact with the participant(where possible, 3 telephone calls and, if necessary, a certified letterto the participant’s last known mailing address or local equivalentmethods). These contact attempts should be documented in theparticipant’s medical record or study file.

Should the participant continue to be unreachable, he or she will beconsidered to have withdrawn from the study with a primary reason oflost to follow-up.]

Study Assessments and Procedures

The following evaluations will be performed during the study outlined inthe Schedule of Activities.

Informed Consent Procedures

The Principal Investigator(s) at each site will ensure that the subjectis given full and adequate oral and written information about thenature, purpose, and possible risk and benefit of the study. Subjectsmust also be notified that they are free to discontinue from the studyat any time. The subject should be given the opportunity to askquestions and allowed time to consider the information provided.

The subject’s signed and dated informed consent must be obtained beforeconducting any study procedures.

The Principal Investigator(s) must maintain the original, signedInformed Consent Form. A copy of the signed Informed Consent Form mustbe given to the subject.

Vital Signs

On injection visit, vital signs will be measured within 1 hour prior todosing and within 30 minutes after dosing.

Vital signs will be measured before venipuncture. Vital signs includeblood pressure (BP) and pulse measurements. After the patient has beensitting for 3 minutes, with back supported and both feet placed on thefloor, systolic and diastolic BP will be measured using an automatedvalidated device, with an appropriately sized cuff. In case the cuffsizes available are not large enough for the patient’s armcircumference, a sphygmomanometer with an appropriately sized cuff maybe used. If vital signs are out- of-range at screening/eligibility, theInvestigator may obtain two additional readings, so that a total of upto three consecutive assessments are made, with the patient seatedquietly for approximately five minutes preceding each repeat assessment.At least the last reading must be within the ranges provided above inorder for the patient to qualify. All of the above tests will beperformed after resting for 3 minutes at all visits.

Height in centimetres (cm) and body weight (to the nearest 0.1 kilogram[kg] in indoor clothing, but without shoes) will be measured at Visit 1(Screening). Body mass index (BMI) will be calculated using thefollowing formula: BMI = Body weight (kg) / [Height (m)]2.

Laboratory Analysis of Blood and Urine

Collection of blood and urine will occur at the study site and thesamples will be shipped to a central laboratory for analysis.

The following clinical labs will be performed: Hematology: Hemoglobin;Hematocrit; Red blood cell (RBC) count; Platelet count; white blood cell(WBC) count with differential; Chemistry: Blood urea nitrogen (BUN);Creatinine; Bilirubin (total, direct and indirect); Albumin; Alkalinephosphatase (ALP); Aspartate aminotransferase (AST); Alanineaminotransferase (ALT); Creatine kinase; Glucose; Electrolytes (sodium,potassium, chloride, bicarbonate); Urinalysis: pH; Specific gravity;Protein; Glucose; Ketones; Bilirubin; Blood; Nitrite; Urobilinogen;Leukocyte esterase; Other: Human chorionic gonadotropin (HCG) a;Follicle-stimulating hormone (FSH) b; Luteinizing hormone (LH) b.

The Investigator must review the results of the Screening Visit clinicallaboratory tests (including recheck results) and confirm that theseresults do not show evidence of any medical condition that would makestudy participation inappropriate. The Investigator should also assessany changes from baseline at the follow up visits and the Exit Visit.

Notes: a. Serum Pregnancy Test (i.e. HCG) will be performed for femalesof child bearing potential at screening only.b. FSH and LH will beperformed for postmenopausal females at screening only.

Urine Pregnancy Test

Urine pregnancy test will be performed in WOCBP only as outlined in theStudy Flow Chart.

Best-Corrected Visual Acuity

Best-corrected visual acuity (including LL-BCVA) testing, performed by acertified VA examiner, should precede any examination requiringadministration of eye drops to dilate the eye or any examinationrequiring contact with the eye. ETDRS best-corrected visual acuity(BCVA) will be obtained in each eye separately at screening (Visit 1).This assessment is to be performed prior to pupil dilation. The numberof letters read correctly (for each eye) will be recorded in theappropriate study document. For the remainder of study visits (Visits2-8), BCVA will only be obtained in the study eye.

Complete Ophthalmic Exam

The complete ophthalmic exam will consist of the following: Externalexamination of the eye and adnexa; Routine screening for eyelids/pupilresponsiveness (including ptosis, abnormal pupil shape, unequal pupils,abnormal reaction to light and afferent pupillary defect); Slit-lampexamination [cornea, anterior chamber, iris, lens, aqueous reaction(cells and flare). If an abnormal lens finding is noted during theslit-lamp examination, at any visit, then the finding should be furthercharacterized with LOCS III. All subsequent visits for that subjectshould include LOCS III. A complete description of LOCS III standardizedprocedures and grading scales is outlined in the MOP; Dilated fundusexam including evaluation of retina and vitreous (i.e. posterior segmentabnormalities, retinal hemorrhage/detachment, and vitreal hemorrhagedensity and vitreous cells); Vitreal hemorrhage density and vitreouscells grading scales; Intraocular pressure (IOP) will be measured inboth eyes at Visit 1 as per the study site’s regular practice andrecorded in the appropriate study document. For the remainder of studyvisits (Visits 2-9), IOP will only be obtained in the study eye.

Ocular Imaging

The following ocular images will be obtained as outlined in the visitschedule above, also see SOA: Digital Color Fundus Photograph;Fluorescein angiography; Spectral Domain Optical coherence tomography;Fundus Autofluorescence; Infrared reflectance imaging. Only done atselected clinical sites with Heidelberg Spectralis® system.

Post-Injection Assessment

The study eye will be assessed before and after injection to ensure thatthe injection procedure and/or the study medication have not endangeredthe health of the eye. The initial post-injection assessment should bedone within 15 minutes post-injection and include a gross assessment ofvision (light perception) and monitoring IOP. If subject passes grossvision test and IOP is < 30 mmHg, the subject may leave the site. Ifsubject fails gross vision test and/or IOP is > 30 mmHg, assessmentswill continue every approximately 30 minutes until the subject passesgross vision test and IOP is 30 mmHg.

Any subject who develops a significant and sustained raise in IOP (> 30mmHg) or a non-adequately perfused central retinal artery (CRA) afterinjection, should be monitored according to the PI’s clinical judgmentand may undergo additional procedures and measurements of IOP beyondthose specified in the protocol as well as IOP lowering procedures. Ifany concern or immediate toxicity is noted, the subject will remain atthe site and will be treated according to the PI’s clinical judgment.

Blood Volume for Study Assessments

Blood volume during study (up to Day 150), see Table 10.

Adverse Events and Serious Adverse Events

All adverse events (AEs) (as defined above), either observed by the PIor one of their medical collaborators, or reported by the participantspontaneously, or in response to direct questioning, will be reported.All adverse events (ocular, non-ocular, serious, non-serious,volunteered, and elicited) must be documented in study records.

Definition of Adverse Events (ae)

An adverse event is any untoward medical occurrence in a subject whoreceives a pharmaceutical product. The occurrence does not necessarilyhave to have a causal relationship with the treatment. Therefore, an AEcan be any unfavorable and unintended sign, symptom, or diseasetemporally associated with the use of a drug, whether or not consideredrelated to the drug.

Note: For purposes of this study, abnormal laboratory values will not beconsidered adverse events unless deemed clinically significant by theInvestigator. All abnormal laboratory values will be recorded in thedatabase and appropriate analyses presented in the final study report.

Definition of Serious Adverse Events (se)

A serious adverse event (SAE) is defined as any untoward medicaloccurrence that at any dose: Results in death; is life-threatening: thismeans that the subject was at risk of death at the time of the event; itdoes not mean that the event might have caused death had it occurred ina more severe form; Required hospitalization or prolongation of existinghospitalization; results in persistent or significant incapacity orsubstantial disruption of the ability to conduct normal life functions;or is a congenital anomaly or birth defect.

Important medical events that may not result in death, belife-threatening, or require hospitalization may be considered seriouswhen, based upon appropriate medical judgment, they may jeopardize thepatient or subject and may require medical or surgical intervention toprevent one of the outcomes listed in the above definition.

Medical and scientific judgment should be exercised in deciding if an AEis serious and if expedited reporting is appropriate.

Adverse Events of Special Interest

An adverse event of special interest is one of scientific and medicalconcern specific to the Sponsor’s product or program where ongoingmonitoring and rapid communication by the Investigator to the Sponsormay be appropriate. These adverse events may be serious or non-serious.Applicable adverse events may require further investigation in order tocharacterize and understand, and depending upon the nature of the event,rapid communication by the trial Sponsor to other parties may also berequired. These adverse events of special interest must be reportedusing the same mechanism and timeframe (i.e. within one working day ofthe Investigator’s or delegate’s knowledge of the event) as describedfor serious adverse events. The adverse events of special interestinclude the following: Endophthalmitis; 4+ ocular inflammation; 2-3+ocular inflammation that fails to decrease to 1+ or less within 30 daysof the onset of the event; Sustained (> 5 minutes) loss of lightperception after FCA injection; Sustained elevation of IOP (30 mmHg)at/past 90 minutes’ post-injection; Any elevation of IOP requiringsurgical intervention (i.e. paracentesis); new vitreous hemorrhage of >2+ severity that does not resolve within 14 days of the onset of theeven; cataract progression.

If an adverse event of special interest occurs in a study subject, thestudy subject will be followed for resolution of the adverse event. Adecision will be made by the Sponsor concerning further exposure to thestudy treatment and further participation in the study.

Adverse Event Assessment and Recording

The Investigator will probe, via discussion with the subject, for theoccurrence of AEs during each subject visit and record the informationin the site’s source documents. For each AE, the PI should note thestart and resolution dates, the severity, whether it meets thedefinition of an SAE, the relationship of the event to the study drug,the action taken regarding study drug, and the outcome of the event.Data should be transcribed from the source documents to the CRF as perthe CRF instructions.

When reporting an adverse event, the event description should use thebest matching terminology describing the event as found in the “CommonTerminology Criteria for Adverse Events” (CTCAE, v 4.03). If anavailable CTCAE term fits the event well, no additional descriptors maybe needed.

However, the Investigator should add any necessary descriptions in orderto clarify the event or to place it in an appropriate context. If anappropriate term matching the adverse event cannot be found in the CTCAEand you do not know the preferred MedDRA term, the adverse eventdescription should include a diagnosis, sign or symptom with additionalinformation to facilitate subsequent categorization into MedDRA codingterms

Intensity

The PI must grade the severity of all reported adverse events into oneof five categories: Grade 1 (Mild), Grade 2 (Moderate), Grade 3(Severe), Grade 4 (Life- Threatening) or Grade 5 (Death related to AE).The standardized CTCAE severity grading scales for the specific type ofadverse event reported must be used when a matching CTCAE term isavailable. If no reference to a standard grading scale applies or isimmediately available, use the following guideline:

GRADE 1 -MILD: Persistence of any otherwise insignificant medicaloccurrence beyond 72 hours or any transient (< 72 hours) AE consideredby the PI to be related to the study drug. No or minimal medical therapyor intervention required, hospitalization not necessary, no or littlelimitation in normal activities; non-prescription or single-useprescription therapy may be employed to relieve symptoms. Mild adverseevents may be listed as expected consequences of the therapy for anygiven protocol, and standard supportive measures for such an expectedevent do not necessarily elevate the event to a higher grade.

GRADE 2- MODERATE: Mild to moderate limitation in activity, someassistance may be needed; possibly none but usually minimalintervention/therapy required, hospitalization possible.

GRADE 3- SEVERE: Marked limitation in activity, some assistance usuallyrequired; medical intervention/therapy required; hospitalizationpossible or likely. [Specifically, for ocular adverse events in thisvision related study, an immediately sight-threatening condition (e.g.,impending corneal perforation, retinal detachment) may be categorized asGrade 3 if it would lead to total blindness in the affected eye(s).]

GRADE 4- LIFE THREATENING: Extreme limitation in activity, significantand immediate assistance required; significant medical/therapyintervention required to prevent loss of life; hospitalization,emergency treatment or hospice care probable. This grade is used whenthe participant was, in the view of the PI, at substantial risk of dyingat the time of the adverse event or it was suspected that use orcontinued use of the test article would have resulted in theparticipant’s death. (This does not include a reaction that, had itoccurred in a more serious form, might have caused death. For example,drug-induced hepatitis that resolved without evidence of hepatic failurewould not be considered life-threatening even though drug-inducedhepatitis can be fatal.)

GRADE 5- DEATH: Death related to AE.

Causality

The PI (or an authorized study physician) must submit an attribution forcausality of the reported adverse event to the test article orprocedure.

The attribution should take into account both the temporal associationand any known physical, physiological or toxicological informationregarding the test article that could reasonably infer causality.Causality should only be considered for the experimental test articleand not for any standard study examination or diagnostic procedures. Thefour attribution categories are: Unrelated -Does not follow a reasonabletemporal sequence from the administration of study drug. The event orlaboratory test abnormality is clearly due to extraneous causes(disease, other drugs, environment, etc.) Unlikely related - Does notfollow a known pattern of response to study drug. Does not follow areasonable temporal sequence from the administration of study drug.Disease or other drugs provides plausible explanation.

It does not reappear or worsen when study drug is re-administeredPossibly related -Follows a known pattern of response to study drug.Time sequence from administration of the study drug is reasonable. Couldalso be explained by disease or other drugs. Probably related - Followsa known pattern of response to study drug. Time sequence fromadministration of the study drug is reasonable. Response to withdrawalclinically reasonable. Cannot be reasonably explained by the knowncharacteristics of the participant’s clinical state, environmentalfactors, or other therapies administered to the subject.

Serious Adverse Event Reporting

All SAEs (defined herein), whether judged related or not to studymedication, will be reported to the Sponsor (or designated MedicalMonitor) by telephone, e-mail or facsimile within 24 hours of theInvestigator becoming aware of such SAEs. The contact details can befound of the serious adverse event form.

The initial SAE Report should include, at a minimum, the followinginformation: Protocol number; Site number; Subject screening number,initials, gender, and date of birth; Name of PI and investigator siteaddress; Details of SAE; Criterion for classification as “serious”; Dateof SAE onset.

Follow-up SAE reports should be submitted as further information becomesavailable, and the final SAE Report should include information on theSAE intensity, outcome, and relationship to study drug; dates of studydrug administration, concomitant medications, and any other relevantinformation. The PI should also provide clear copies of supportingdocuments as necessary (e.g. hospital discharge summary, laboratoryreports, autopsy reports, etc.), with the subject’s personal identifiersremoved. All SAEs will be followed until the acute event has resolved,even if the subject discontinues study participation prior to theresolution. The Investigator must report SAEs occurring at his/her siteto the IRB/IEC as required.

Expected Adverse Events Expected AE Related to the Test Article:

No ocular or systemic AE related to the investigational drug areexpected at the doses proposed in this protocol.

Expected AE Related to the IVT Injection Procedure:

Mild discomfort related to the injection procedure (including use of aneyelid speculum, anaesthetic drops, mydriatic drops, antibiotic drops,povidone-iodine drops or flush and subconjunctival injection ofanaesthetic, as well as the actual insertion of the IVT needle) areexpected. These procedure-related adverse events include but are notlimited to: redness, mild eye pain, eye irritation, visual disturbance,abnormal sensation in the eye, etc. and will be graded as indicatedherein

Disease Progression

A condition considered by the PI as unequivocal AMD disease progressionin the study eye or fellow eye should be identified as such in theparticipant’s source documents and should not be recorded as an adverseevent in the CRF, such as lesion growth, lesion bleeding, lesion thatexudes fluid, an RPE tear, and extensive deposition of lipid. All otherconditions should be recorded as an adverse event. The unequivocalnature of the disease progression must be indicated in the sourcedocuments. Normal progression or worsening of the medical conditionunder study (e.g. vision loss due to the progression of AMD), by itself,does not necessarily constitute an adverse event unless the change canbe reasonably attributed to an action of the test article and not onlyto its lack of efficacy.

Withdrawal

Participants may choose to withdraw from this study for any reason atany time without penalty or prohibition from enrolling in other clinicalprotocols.

Participant wishing to withdraw from the study completely will beoffered an early termination visit.

This early termination visit will include the examinations outlinedherein.

Pregnancy in the Clinical Trial

WOCBP are not excluded from the study as long as adequate birth controlmethods are being utilized. Prior to enrolment in the clinical trial,WOCBP must be advised of the importance of avoiding pregnancy during thetrial and the potential risks associated with an unintentionalpregnancy. WOCBP and males with partners who are WOCBP will beinstructed to practice an acceptable method of birth control (as definedabove) for the duration of the study. Male subjects will be counselledto avoid donating sperm after dosing on Day 1 until the final Exitvisit.

During the trial, female subjects are to be instructed to contact theInvestigator immediately if they suspect they might be pregnant. Thestudy Sponsor must be contacted immediately and a decision will be maderegarding continuation of the pregnant woman in the study based upon thecircumstances surrounding the pregnancy. Pregnancy is not reportable asan adverse event; however, complications may be reportable. If a femalesubject or partner of a male subject becomes pregnant during the study,the PI should report the pregnancy to the Medical Monitor within 24hours of being notified. The Investigator should follow the pregnancyuntil completion. At the completion of the pregnancy, the Investigatorwill document and report the outcome. If the outcome of the pregnancymeets the criteria for classification as an SAE (i.e. postpartumcomplication, stillbirth, neonatal death, or congenital anomaly) theInvestigator should follow the procedures for reporting an SAE.

Statistical Considerations

Descriptive summaries will include mean, standard deviation, median, andrange for continuous variables and counts and percentages forcategorical variables.

Population for Analysis

Safety Analysis: All subjects who received at least one dose oftreatment will be included in the evaluation of safety of FCA.

Efficacy Endpoint(s): The efficacy analysis will be based on anintention-to-treat population (ITT), which is defined as all subjectswho received the single dose of treatment and have at least one visit ator after month 2. Month 2 is the first visit on treatment at whichlesion area is measured. Per protocol (PP) efficacy analyses willinclude all randomized subjects who return for Day 150 of follow up.

Safety is the main analysis population for safety endpoints, and ITT isthe main analysis population for efficacy endpoints. The assignment ofparticipants to each analysis population will be based on the review ofdata after the completion of all data collection, monitoring by theclinical research associate and first round of query resolution by datamanagement and prior to database lock.

Demographic and Baseline Characteristics

Participant demographic and baseline variables (age, sex, ethnicity,race, height, weight, and BMI) will be summarised with descriptivestatistics. Sex, ethnicity, and race will be summarised with frequencycounts and percentages. Baseline ocular assessments will be summariseddescriptively as well.

Pregnancy test results, concomitant medication and medical history datafor each participant will be presented in data listings. Concomitantmedications will be summarised descriptively by using frequency countsand percentages.

Analysis of Primary Safety Endpoints

No formal inferential statistics will be performed on safetyassessments. Statistical methods for the safety analyses will beprimarily descriptive in nature. The Fludrocortisone acetate 1 mg/0.1 mLand 2 mg/0.1 mL injection will be considered as safe and tolerable basedon the number of subjects presenting severe AEs related to the studydrug. It is understood that safety is a medical judgment that cannot beprospectively defined in detail. However, as general guidance, a subjectwill be considered to have tolerated a dose if the subject experiencesno clinically significant drug-related adverse event or laboratoryabnormality. Conversely, a subject will not be considered to havetolerated the dose if he experiences a clinically significant drug-related adverse event or laboratory abnormality during the study drugadministration or post-administration follow-up period.

Listings and summaries for all safety data will be presented using theSafety Population. Descriptive statistics (mean, SD, median, minimum andmaximum) will be calculated for summaries of continuous safety data andfrequency counts and percentages (where appropriate) will be calculatedfor summaries of discrete/categorical safety data.

Adverse events (AEs) will be coded using the Medical Dictionary forRegulatory Activities (MedDRA), and data will be summarised by System,Organ, Class and preferred term. The number and percent of participantsreporting each AE will be summarised descriptively (n=9). A participantwith two or more AEs within the same level of summarisation (i.e.,system, organ, class or preferred term) will be counted only once inthat level. The number of AEs reported will also be presented. Adverseevents will also be summarised by severity as well as relationship tostudy treatment. A by-participant AE data listing, including verbatimterm, preferred term, system organ class, severity, and relationship tostudy treatment, will be provided. Separate listings will be generatedfor SAEs and AEs leading to study/treatment discontinuation.

All haematology, blood chemistry and urinalysis (continuous variables)parameters will be summarised using descriptive statistics for all studyvisits assessed, including change from baseline (last pre-surgery value)for all post-surgery assessments. All laboratory data will be includedin the data listings and all test values outside the normal range willbe flagged.

All vital sign parameters will be summarised using descriptivestatistics by study visit, including change from baseline (lastpre-surgery) for all post-surgery assessments.

Individual vital sign assessments will be listed for each participant.Findings of physical examinations will be listed for each participantand summarised descriptively by using count and percentage by studyvisit.

Analysis of Secondary Endpoints

The efficacy endpoints are the secondary endpoints of this study, whichinclude complete ocular examination.

ETDRS best-corrected visual acuity (BCVA) will be scored with referenceto the Early Treatment Diabetic Retinopathy Study ETDRS letters). ETDRSwill be treated as continuous data, and descriptive statistics (mean,SD, median, minimum and maximum) will be summarised for ETDRS observedvalue and change from baseline at each post-surgery visit. Exploratoryanalysis of ETDRS change over time will be assessed by using a mixedmodel. The correlations between repeated measures of the sameparticipant will be accounted for by the mixed model. The least squaresmean of ETDRS change from baseline and its 95% confidence interval ateach visit will be estimated. Similar analyses will be conducted forintraocular pressures. Categorical efficacy endpoints such as slit lampbiomicroscopy exam findings, dilated ophthalmoscopy exam findings, colorfundus photography and OCT finding will be summarised descriptively byfrequency count and percentage (proportion) where appropriate.

Interim Analysis

There is no formal interim analysis planned for this study.

Sample Size

The study is planned to enrol up to 12 participants.

The sample size chosen for this study was selected without formalstatistical justification, but the numbers chosen are consideredadequate for assessing the study objectives. The sample size wasdetermined on the basis of practical and logistical considerations andnot based on statistical power with regard to hypothesis testing orprecision with regard to parameter estimation.

This phase 1 trial was designed to identify any important limitingtoxicities and to determine if this dose is suitable for phase 2 trial.This was also designed to minimize the likelihood that a minimum numberof subjects will be exposed to the investigational drug.

This is an open label study, and no randomization is conducted in thisstudy.

Missing Data

Missing data will generally not be imputed for safety or efficacy data.

Data Collection, Retention and Monitoring Data Collection Instruments

The investigator will prepare and maintain adequate and accurate sourcedocuments designed to record all observations and other pertinent datafor each participant treated with the study drug.

Study personnel at each site will enter data from source documentscorresponding to a participant’s visit into the protocol-specificelectronic Case Report Form (eCRF) when the information corresponding tothat visit is available. Participants will not be identified by name inthe study database or on any study documents to be collected by theSponsor (or designee), but will be identified by a site number,participant number and initials.

If a correction is required for an eCRF, the time and date stamps trackthe person entering or updating eCRF data and creates an electronicaudit trail. The Investigator is responsible for all informationcollected on participants enrolled in this study. All data collectedduring the course of this study must be reviewed and verified forcompleteness and accuracy by the Investigator. A copy of the CRF willremain at the Investigator’s site at the completion of the study.

DATA MANAGEMENT PROCEDURES

The data will be entered into a validated database. The Data Managementgroup will be responsible for data processing, in accordance withprocedural documentation. Database lock will occur once qualityassurance procedures have been completed.

All procedures for the handling and analysis of data will be conductedusing good computing practices meeting FDA guidelines for the handlingand analysis of data for clinical trials.

Data Quality Control and Reporting

After data have been entered into the study database, a system ofcomputerised data validation checks will be implemented and applied tothe database on a regular basis.

Queries are entered, tracked, and resolved through the EDC systemdirectly. The study database will be updated in accordance with theresolved queries. All changes to the study database will be documented.

Archival Data

The database is safeguarded against unauthorised access by establishedsecurity procedures; appropriate backup copies of the database andrelated software files will be maintained. Databases are backed up bythe database administrator in conjunction with any updates or changes tothe database.

At critical junctures of the protocol (e.g., production of interimreports and final reports), data for analysis is locked and cleaned perestablished procedures.

Availability and Retention of Investigational Records

The Investigator must make study data accessible to the monitor, otherauthorized representatives of the Sponsor (or designee), IRB/IEC, andRegulatory Agency (e.g., FDA, TGA) inspectors upon request. A file foreach participant must be maintained that includes the signed informedConsent, HIPAA Authorization and Assent Form and copies of all sourcedocumentation related to that participant. The Investigator must ensurethe reliability and availability of source documents from which theinformation on the eCRF was derived.

All study documents (patient files, signed informed consent forms,copies of eCRFs,

Study File Notebook, etc.) must be kept secured for a period of fifteenyears following the completion of the study.

Monitoring

Monitoring visits will be conducted by representatives of the Sponsoraccording to the U.S. CFR Title 21 Parts 50, 56, and 312 and ICHGuidelines for GCP (E6). By signing this protocol, the investigatorgrants permission to the Sponsor (or designee), and appropriateregulatory authorities to conduct on-site monitoring and/or auditing ofall appropriate study documentation.

Data Safety Monitoring Board

An independent DSMB will be convened. The mission of the DSMB will be toensure the ethical conduct of the trial and to protect the safetyinterests of patients in this study.

The DSMB will be responsible for reviewing the cumulative safety resultsfrom the study. The DSMB will meet prior to the commencement of thestudy, and will review all available safety/tolerability data (e.g.,adverse events, serious adverse events, clinical laboratory assessments,blood pressure, haematology, urology) at Day 0 and 1 month after IVTinjection of FCA of the initial participant in Part 1 and 3 (prior toPart 2 & 4 of the study), and convene as required throughout the studyperiod to review data and potential safety risks. The criteria forevaluating study continuation will relate to study safety, including theincidence and severity of ocular and/or systemic side effects notlimited to but including; change in IOP of >10 mmHg, a loss of 15letters or more in BCVA, presence or intraocular inflammation, presenceor absence of ocular pain, change in BP of 30 mmHg (systolic ordiastolic), incidence of hospitalisation or systemic illness, and anyother ocular or systemic adverse events reported. Any changes will bereferenced to baseline measurements. The DSMB will then meet at theconclusion of the study and after the final statistical analysis inorder to review all data.

DSMB will consist an ophthalmologist, and a biostatistician, bothindependent of the study team.

Participant Confidentiality

In order to maintain participant confidentiality, only a site number,participant number and participant initials will identify all studyparticipants on eCRFs and other documentation submitted to the Sponsor.Additional participant confidentiality issues (if applicable) arecovered in the Clinical Study Agreement.

Administrative, Ethical, Regulatory Considerations

The study will be conducted according to the Declaration of Helsinki,Protection of Human Volunteers (21 CFR 50), Institutional Review Boards(21 CFR 56), and Obligations of Clinical Investigators (21 CFR 312).

To maintain confidentiality, all laboratory specimens, evaluation forms,reports and other records will be identified by a coded number andinitials only. All study records will be kept in a locked file cabinetand code sheets linking a patient’s name to a patient identificationnumber will be stored separately in another locked file cabinet.Clinical information will not be released without written permission ofthe participant, except as necessary for monitoring by the TGA. TheInvestigator must also comply with all applicable privacy regulations(e.g., The Health Records and Information Privacy Act 2002).

Protocol Amendments

Any amendment to the protocol will be written by the Sponsor. Protocolamendments cannot be implemented without prior written IRB/IEC approvalexcept as necessary to eliminate immediate safety hazards to patients. Aprotocol amendment intended to eliminate an apparent immediate hazard topatients may be implemented immediately, provided the IRBs are notifiedwithin five working days.

Institutional Review Boards and Independent Ethics Committee

The protocol and consent form will be reviewed and approved by theIRB/IEC of each participating centre prior to study initiation. Seriousadverse events regardless of causality will be reported to the IRB/IECin accordance with the standard operating procedures and policies of theIRB/IEC, and the Investigator will keep the IRB/IEC informed as to theprogress of the study. The Investigator will obtain assurance of IRB/IECcompliance with regulations.

Any documents that the IRB/IEC may need to fulfil its responsibilities(such as protocol, protocol amendments, Investigator’s Brochure, consentforms, information concerning patient recruitment, payment orcompensation procedures, or other pertinent information) will besubmitted to the IRB/IEC. The IRB/IECs written unconditional approval ofthe study protocol and the informed consent form will be in thepossession of the Investigator before the study is initiated. TheIRB/IECs unconditional approval statement will be transmitted by theInvestigator to the Sponsor or designee prior to the shipment of studysupplies to the site. This approval must refer to the study by exactprotocol title and number and should identify the documents reviewed andthe date of review.

Protocol and/or informed consent modifications or changes may not beinitiated without prior written IRB/IEC approval except when necessaryto eliminate immediate hazards to the patients or when the change(s)involves only logistical or administrative aspects of the study. Suchmodifications will be submitted to the IRB/IEC and written verificationthat the modification was submitted and subsequently approved should beobtained.

The IRB/IEC must be informed of revisions to other documents originallysubmitted for review; serious and/or unexpected adverse events occurringduring the study in accordance with the standard operating proceduresand policies of the IRB; new information that may affect adversely thesafety of the patients of the conduct of the study; an annual updateand/or request for re-approval; and when the study has been completed.

Informed Consent Form (icf)

Informed consent will be obtained in accordance with the Declaration ofHelsinki, ICH GCP, US Code of Federal Regulations for Protection ofHuman Subjects (21 CFR 50.25 [a,b], CFR 50.27, and CFR Part 56, SubpartA), the Health Insurance Portability and Accountability Act (HIPAA, ifapplicable), and local regulations.

The present invention is of significant advantage because the improvedphysicochemical property may improve the required course of therapy forexample, in reducing the number of intraocular injections required orincreasing the period between intraocular injections and/or improve theease of injection.

Additionally, the present invention is of significant advantage becausethe decreased number of injections or increased period betweenobjections may lead to increased patient compliance. This in turn willlead to improved ocular health outcomes.

This present invention is of particular advantage over prior artmulti-dose formulations which result in significant waste whenregulations only allow one use of a multi-dose vial. Additionally, thepre-filled syringe is convenient for the health-care provider performingthe injection and it’s ease of handling may reduce error.

The tailored, single unit dose of the present claimed invention issafer, more cost effective and more accurate than conventionalmulti-dose formulations.

Throughout the specification the aim has been to describe the preferredembodiments of the invention without limiting the invention to any oneembodiment or specific collection of features. It will therefore beappreciated by those of skill in the art that, in light of the instantdisclosure, various modifications and changes can be made in theparticular embodiments exemplified without departing from the scope ofthe present invention.

TABLE 1 Mineralocorticoid Receptor and Glucocorticoid Receptor activityof some corticosterones Compound GR potency MR potency Duration ofaction (t_(½) in hours) Hvdrocortisone (cortisol) 1 1 8 Cortisone 0.80.8 oral 8; i.m. 18+ Prednisone 3.5-5 0.8 16-36 Prednisolone 4 0.8 16-36Methylprednisolone 5-7.5 0.5 18-40 Dexamethasone 25-80 0 36-54Betamethasone 25-30 0 36-54 Triamcinolone 5 0 12-36 Beclometasone 8puffs 4 times a day; equals 14 mg oral prednisone once/day - -Fludrocortisone acetate 15 200 24 Deoxycorticosterone acetate (DOCA) 020 - Aldosterone 0.3 200-1000 - Key: MR = mineralocorticoid receptor; GR= glucocorticoid receptor; i.m. intramuscular

TABLE 2 Measure Particle Size Distribution Drug D(v,0.5) micronsD(v,0.9) microns 11-DC 81 233 DCS 22 80 DCSA 52 226 FLU 4 10 TA 5 11

TABLE 3 Suspension of compounds Suspension with CMC and Tween 80Suspension without CMC and Tween 80 Suspension quality Drawing-upExpelling Suspension quality Drawing-up Expelling Homogenous suspension,No flocculation or layer Separation Easy to draw-up all formulation(Excellent) Easy to expel (Excellent) Two layers obviously Separated 1-Top transparent liquid layer(water) 2- Bottom white solid layer(particles) Easy to draw-up but you may need to shake very well beforedrawn Easy to expel Homogenous suspension, No flocculation or layerSeparation Easy to draw-up all formulation (Excellent) Easy to expel(Excellent) Two layers obviously separated 1- Top transparent liquidlayer(water) 2- Bottom white solid layer (particles) Easy to draw-up butyou may need to shake very well before drawn Easy to expel Homogenoussuspension, No flocculation or layer Separation Easy to draw-up allformulation (Excellent) Easy to expel (Excellent) Two layers obviouslyseparated 1- Top foamy white layer (particles) 2- Bottom liquidtransparent (water) Easy to draw-up, but not all formulation up becauseof homogeneity Easy to expel Homogenous suspension No flocculation orlayer separation Easy to draw-up all formulation (Excellent) Easy toexpel (Excellent) Homogenous suspension No flocculation or layerseparation Easy to draw-up all formulation Easy to expel Homogenoussuspension, No flocculation or layer separation Easy to draw-up allformulation (Excellent) Easy to expel (Excellent) Two layers obviouslyseparated 1- Top foamy white layer (particles) 2- Bottom liquidtransparent (water) Easy to draw- up, but not all formulation up becauseof homogeneity Easy to expel

TABLE 4 Formulation Utilized Component Function Mass (ml) Tween 80Wetting agent 0.4 mg CMC Viscosity modifier 12.5 mg Drug Active 40 mg

TABLE 5 Summary of batch production results indicating applicability ofmethod Drug 11-DC Test Method ID Specification Result Date testedComments Av Drug RGA40/1 20.0 ± 2.0 mg 18.4 ± 0.5 27/10/2006 PassedContent per vial Particle RGA40/2 D(0.5)=<20 7.1 Mar. 11, 2006 PassedSize D(0.9)=<30 25 pH RGA40/3 6.0 - 8.0 7.0 Mar. 11, 2006 Passed DCSTest Method ID Specification Result Date tested Comments Av Drug RGA40/120.0 ±2.0 mg 18.5± 0.7 Jan. 11, 2006 Passed Content per vial ParticleRGA40/2 D(0.5)=<20 12.7 Mar. 11, 2006 Passed Size D(0.9)=<30 30.0 pHRGA40/3 6.0 - 8.0 7.0 Mar. 11, 2006 Passed DCSA Test Method IDSpecification Result Date tested Comments Av Drug RGA40/1 20.0 ±2.0 mg16 ± 0.9 Feb. 11, 2006 Failed• Content per vial Particle RGA40/2D(0.5)=<20 8.25 Mar. 11, 2006 Passed Size D(0.9)=<30 26.77 pH RGA40/36.0 - 8.0 7.0 Mar. 11, 2006 Passed Fludra Test Method ID SpecificationResult Date tested Comments Av Drug RGA40/1 20.0 ± 2.0 mg 18.1 ± 0.725/10/2006 Passed Content per vial Particle RGA40/2 D(0.5)=<20 3.47 Mar.11, 2006 Passed Size D(0.9)=<30 9.16 pH RGA40/3 6.0 - 8.0 7.0 Mar. 11,2006 Passed T.A Test Method ID Specification Result Date tested CommentsAv Drug RGA40/1 20.0 ± 2.0 mg 18.33 ± 0.7 30/10/2006 Passed Content pervial Particle RGA40/2 D(0.5)=<20 4.43 Mar. 11, 2006 Passed SizeD(0.9)=<30 8.57 pH RGA40/3 6.0 - 8.0 7.0 Mar. 11, 2006 Passed

TABLE 6 Composition of Triesecence Triamcinolone acetonide 40 mg/mLcarboxymethylcellulose sodium 0.5% w/v; 5 mg/mL polysorbate 80 0.015%(not stipulated but expect w/v = 1.5 mg/mL sodium chloride to isotonicpotassium chloride, calcium chloride (dehydrate), magnesium chloride(hexahydrate), sodium acetate (trihydrate), sodium citrate (dihydrate)levels not stipulated, but suspect BSS composition?? hydrochloric acidand/ or sodium hydroxide for pH adjustment Water for injection Qs

TABLE 7 Kenalog Composition Triamcinolone acetonide 10 mg/mLcarboxymethylcellulose sodium 0.75% w/v; 7.5 mg/mL polysorbate 80 0.04%(not stipulated but expect w/v = 0.4 mg/mL sodium chloride 0.65% toisotonic benzyl alcohol 0.9% (w/v) hydrochloric acid and/ or sodiumhydroxide for pH adjustment Water for injection qs

TABLE 8 Schedule of Activities Procedures Screenign Day-14 to-1 BaselineVisit 1, Day 0 Study Visit 2 Day 1 +/-1 day Study Visit 3 Day 7 +/-1 dayStudy Visit 4 Day 14 +/-1 day Study Visit 5 Day 28 +/-1 day Study Visit6 Day 60 +/-1 day Study Visit 7 Day 90 +/-1 day Final Study Visit 8 Day150 +/-1 day Informed consent X Demographics X Medical history XConcomitant Medications X X X X X X X X X Adverse event review X X X X XX X Administer study intervention X Physical exam X X X X X Vital signsX X X X X X X X X Best corrected visual acuity (BCVA) X X X X X X X X XHeight and Weight X X X Visual Function Questionnaire (VFQ-25) X XGoldmann Intraocular Pressure (IOP) X X X X X X X X X Slit lampbiomicroscopy, incl. lens grading X X X X X X X X X Dilatedophthalmoscopy X X X X X X X X X SD-OCT X X X X X X X X X FAF and NIFR XX X X X X X X X Colour Fundus Photography X X X Fluorescein angiogram XX Haematology & Urinalysis X X X X X Serum chemistry ^(a) X X X X XUrine Pregnancy test ^(b) X X Pharmacokinetic sampling X X X X CompleteCase Report Forms (CRFs) X X X X X X X X X a: Albumin, alkalinephosphatase, total bilirubin, bicarbonate, BUN, calcium, chloride,creatinine, glucose, LDH, phosphorus, potassium, total protein, AST,ALT, sodium. b: Serum pregnancy test (women of childbearing potential).

TABLE 9: Treatment Arm Dose Escalation Part 1 Fludrocortisone acetate 1mg/0.1 mL at Day 0 If no dose limiting toxicity is observed in 3patients at this given dose level, the dose will be escalated to thefollowing level: Part 2 Fludrocortisone acetate 2 mg/0.1 mL at Day 0

TABLE 10: Assay Number of Time Points Approximate Volume per Time Point(mL) Approximate Sample Volume Over Course of Study (mL)Pharmacokinetics 4/9 4 36 Haematology 5/9 4 36 Chemistry (Incl.HCG/LH/FSH) 5/9 8.5 76.5

1. A medical device comprising a unit dose pharmaceutical composition,the unit dose comprising: 2.0 to 8.0 mg of a dry powder offludrocortisone acetate and/or triamcinolone acetonide; wherein the unitdose pharmaceutical composition is comprised in a syringe.
 2. Themedical device of claim 1 for use or when used in the treatment of aneye disease or condition or predisposition thereto.
 3. The medicaldevice of claim 1 wherein no increase in intraocular pressure occurs asa result of injection of the unit dose pharmaceutical composition. 4.The medical device of claim 1 wherein intraocular pressure is maintainedafter injection of the unit dose pharmaceutical composition.
 5. A methodof treatment of an eye disease or condition or a predisposition theretoin a subject in need thereof, the method including injecting into theeye a unit dose pharmaceutical composition, the unit dose pharmaceuticalcomposition comprising: 2.0 to 8.0 mg of a dry powder of fludrocortisoneacetate and/or triamcinolone acetonide; wherein the unit dosepharmaceutical composition is comprised in a syringe.
 6. The method ofclaim 5, wherein the injection comprises intravitreal and/orsuprachoroidal injection.
 7. The method of claim 5, wherein theinjection uses a double-barrelled syringe and the first barrel and asecond barrel are injected substantially simultaneously.
 8. The methodof claim 5 wherein no increase in intraocular pressure occurs as aresult of injection of the unit dose pharmaceutical composition.
 9. Themethod of claim 5 wherein intraocular pressure is maintained afterinjection of the unit dose pharmaceutical composition.